Amino acid conjugates providing for sustained systemic concentration of gaba analogues

ABSTRACT

Compounds that provide for sustained systemic concentrations of GABA analogs following oral administration to animals are disclosed. Pharmaceutical compositions including, and methods using, such compounds are also disclosed.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention is directed to compounds that provide for sustainedsystemic concentrations of GABA analogs following administration toanimals. This invention is also directed to pharmaceutical compositionsincluding and methods using such compounds.

2. State of the Art

Rapid clearance of drugs from the systemic circulation represents amajor impediment to effective clinical use of therapeutic and/orprophylactic compounds. Although multiple factors can influence thesystemic concentrations of drugs achieved following administration(including drug solubility, dissolution rate, first-pass metabolism,p-glycoprotein and related efflux mechanisms, hepatic/renal elimination,etc), rapid systemic clearance is a particularly significant reason forsuboptimal systemic exposure to many compounds. Rapid systemic clearancemay require that large doses of drug be administered to achieve atherapeutic or prophylactic effect. Such larger doses of the drug,however, may result in greater variability in drug exposure, morefrequent occurrence of side effects, or decrease in patient compliance.Frequent drug administration may also be required to maintain systemicdrug levels above a minimum effective concentration. This problem isparticularly significant for drugs that must be maintained in awell-defined concentration window to provide continuous therapeutic orprophylactic benefit while minimizing adverse effects (including forexample, antibacterial agents, antiviral agents, anticancer agents,anticonvulsants, anticoagulants, etc.).

Conventional approaches to extend the systemic exposure of drugs withrapid clearance involve the use of formulation or device approaches thatprovide a slow or sustained release of drug within the intestinal lumen.These approaches are well known in the art and normally require that thedrug be well absorbed from the large intestine, where such formulationsare most likely to reside while releasing the drug. Drugs that areamenable to conventional sustained release approaches must be orallyabsorbed from the intestine and typically traverse this epithelialbarrier by passive diffusion across the apical and basolateral membranesof the intestinal epithelial cells. The physicochemical features of amolecule that favor its passive uptake from the intestinal lumen intothe systemic circulation include low molecular weight (e.g. <500 Da),adequate solubility, and a balance of hydrophobic and hydrophiliccharacter (log P generally 1.5-4.0) (Navia and Chaturvedi, P. R. DrugDiscovery Today 1996, 1, 179-189).

Polar or hydrophilic compounds are typically poorly absorbed through ananimal's intestine as there is a substantial energetic penalty forpassage of such compounds across the lipid bilayers that constitutecellular membranes. Many nutrients that result from the digestion ofingested foodstuffs in animals, such as amino acids, di- andtripeptides, monosaccharides, nucleosides and water-soluble vitamins,are polar compounds whose uptake is essential to the viability of theanimal. For these substances there exist specific mechanisms for activetransport of the solute molecules across the apical membrane of theintestinal epithelia. This transport is frequently energized byco-transport of ions down a concentration gradient. Solute transporterproteins are generally single sub-unit, multi-transmembrane spanningpolypeptides, and upon binding of their substrates are believed toundergo conformational changes, which result in movement of thesubstrate(s) across the membrane.

Over the past 10-15 years, it has been found that a number of orallyadministered drugs are recognized as substrates by some of thesetransporter proteins, and that this active transport may largely accountfor the oral absorption of these molecules (Tsuji and Tamai, Pharm. Res.1996, 13, 963-977). While in most instances the transporter substrateproperties of these drugs were unanticipated discoveries made throughretrospective analysis, it has been appreciated that, in principle, onemight achieve good intestinal permeability for a drug by designing inrecognition and uptake by a nutrient transport system. Drugs subject toactive absorption in the small intestine are often unable to passivelydiffuse across epithelial cell membranes and are too large to passthrough the tight junctions that exist between the intestinal cells.These drugs include many compounds structurally related to amino acids,dipeptides, sugars, nucleosides, etc. (for example, many cephalosporins,ACE inhibitors, AZT, etc).

Gamma (“γ”)-aminobutyric acid (“GABA”) is one of the major inhibitorytransmitters in the central nervous system of mammals. GABA is nottransported efficiently into the brain from the bloodstream (i.e., GABAdoes not effectively cross the blood-brain barrier). Consequently, braincells provide virtually all of the GABA found in the brain (GABA isbiosynthesized by decarboxylation of glutamic acid with pyridoxalphosphate).

GABA regulates neuronal excitability through binding to specificmembrane proteins (i.e., GABA receptors), which results in opening of anion channel. The entry of chloride ion through the ion channel leads tohyperpolarization of the recipient cell, which consequently preventstransmission of nerve impulses to other cells. Low levels of GABA havebeen observed in individuals suffering from epileptic seizures, motiondisorders (e.g., multiple sclerosis, action tremors, tardivedyskinesia), panic, anxiety, depression, alcoholism and manic behavior.

The implication of low GABA levels in a number of common disease statesand/or common medical disorders has stimulated intensive interest inpreparing GABA analogs, which have superior pharmaceutical properties incomparison to GABA (e.g., the ability to cross the blood brain barrier).Accordingly, a number of GABA analogs, with considerable pharmaceuticalactivity have been synthesized in the art (See, e.g., Satzinger et al.,U.S. Pat. No. 4,024,175; Silverman et al., U.S. Pat. No. 5,563,175;Horwell et al., U.S. Pat. No. 6,020,370; Silverman et al., U.S. Pat. No.6,028,214; Horwell et al., U.S. Pat. No. 6,103,932; Silverman et al.,U.S. Pat. No. 6,117,906; Silverman, International Application No. WO92/09560; Silverman et al., International Application No. WO 93/23383;Horwell et al., International Application No. WO 97/29101, Horwell etal., International Application No. WO 97/33858; Horwell et al.,International Application No. WO 97/33859; Bryans et al., InternationalApplication No. WO 98/17627; Guglietta et al., International ApplicationNo. WO 99/08671; Bryans et al., International Application No. WO99/21824; Bryans et al., International Application No. WO 99/31057;Belliotti et al., International Application No. WO 99/31074; Bryans etal., International Application No. WO 99/31075; Bryans et al.,International Application No. WO 99/61424; Bryans et al., InternationalApplication No. WO 00/15611; Bryans, International Application No. WO00/31020; Bryans et al., International Application No. WO 00/50027; andBryans et al, International Application No. WO 02/00209).

Pharmaceutically important GABA analogs include, for example,gabapentin, pregabalin, vigabatrin and baclofen. Gabapentin is alipophilic GABA analog that can pass through the blood-brain barrier,which has been used to clinically treat epilepsy since 1994. Gabapentinalso has potentially useful therapeutic effects in chronic pain states(e.g., neuropathic pain, muscular and skeletal pain), psychiatricdisorders (e.g., panic, anxiety, depression, alcoholism and manicbehavior), movement disorders (e.g., multiple sclerosis, action tremors,tardive dyskinesia), etc. (Magnus, Epilepsia, 1999, 40:S66-S72).Currently, gabapentin is also used in the clinical management ofneuropathic pain. Pregabalin, which possesses greater potency inpre-clinical models of pain and epilepsy than gabapentin is presently inPhase III clinical trials.

Rapid systemic clearance is a significant problem with many GABA analogsincluding gabapentin, which consequently require frequent dosing tomaintain a therapeutic or prophylactic concentration in the systemiccirculation (Bryans et al., Med. Res. Rev., 1999, 19, 149-177). Forexample, dosing regimens of 300-600 mg doses of gabapentin administeredthree times per day are typically used for anticonvulsive therapy.Higher doses (1800-3600 mg/day in divided doses) are typically used forthe treatment of neuropathic pain states.

Sustained released formulations are a conventional solution to theproblem of rapid systemic clearance, as is well known to those of skillin the art (See, e.g., “Remington's Pharmaceutical Sciences,”Philadelphia College of Pharmacy and Science, 17th Edition, 1985).Osmotic delivery systems are also recognized methods for sustained drugdelivery (See, e.g., Verma et al., Drug Dev. Ind. Pharm., 2000,26:695-708). Many GABA analogs, including gabapentin and pregabalin, arenot absorbed via the large intestine. Rather, these compounds aretypically absorbed in the small intestine by the large neutral aminoacid transporter (“LNAA”) (Jezyk et al., Pharm. Res., 1999, 16,519-526). The rapid passage of conventional dosage forms through theproximal absorptive region of the gastrointestinal tract has preventedthe successful application of sustained release oral dosage technologiesto GABA analogs. Thus, there is a significant need for effectivesustained release versions of GABA analogs to minimize increased dosingfrequency due to rapid systemic clearance of these compounds.

Another deficiency with some GABA analogs, including gabapentin, istheir lack of dose-proportional oral bioavailability (see Radulovic etal, Drug Metab. Dispos. 1995, 23, 441-448; Gidal et al, Epilepsy Res.2000, 40, 123-127; Gabapentin Supplementary Basis for Approval,Warner-Lambert, Inc.). Absorption of gabapentin in mammals is subject tosaturation, since the large neutral amino acid transport system haslimited substrate capacity and is localized to the upper part of thesmall intestine, creating an absorption window that restricts theability of the drug to be taken up into the bloodstream. Thus in man,gabapentin oral bioavailability decreases from about 60% at a dose of300 mg to about 35% at a dose of 1600 mg. This leads not only toinefficient use of the administered drug, but also to unpredictable andhighly variable drug levels in patients, particularly at the higherdoses associated with efficacy in the treatment of epilepsy andneuropathic pain (Gidal et al, Epilepsy Res. 1998, 31, 91-99). There is,therefore, a need for derivatives of gabapentin and other GABA analogs,which following oral administration to a patient in need of therapyprovide therapeutically efficacious levels of the GABA analog in theplasma of a patient, where the concentration of the GABA analog inplasma of the patient over time provides a curve of concentration of theGABA analog in the plasma over time, the curve having an area under thecurve (AUC) which is substantially more proportional to the dose of GABAanalog administered, as compared to the proportionality achievedfollowing oral administration of the GABA analog itself. There issimilarly a need for derivatives of gabapentin and other GABA analogs,which following oral administration to a patient in need of therapyprovide therapeutically efficacious levels of the GABA analog in theplasma of a patient, where the concentration of the GABA analog inplasma of the patient over time provides a curve of concentration of theGABA analog in the plasma over time, the curve having a maximum plasmaconcentration (C_(max)) which is substantially more proportional to thedose of GABA analog administered, as compared to the proportionalityachieved following oral administration of the GABA analog itself.

One pathway that might provide for the sustained delivery of drugs withrapid systemic clearance is the proton-coupled peptide transport system(Leibach and Ganaphthy, Ann. Rev. Nutr. 1996, 16, 99-119). Thesetransporters mediate the cellular uptake of small intact peptidesconsisting of two or three amino acids and are found primarily in theintestine and kidney. In the intestine, where small peptides are notwell-absorbed by passive diffusion, the transporters act as a vehiclefor their effective absorption. Transporters in the kidney activelyreabsorb di- and tri-peptides from the glomerular filtrate, therebyincreasing their half-life in the circulation.

Two proton-coupled peptide transporters that have been cloned andcharacterized are PFPT1 and PEPT2. PEPT1 is a low-affinity,high-capacity transporter found primarily in the intestine. The humanPEPT1 consists of 708 amino acids and possesses 12 putativetransmembrane domains. PEPT2, in contrast, is a high-affinity,low-capacity transporter found mostly in the kidney. It consists of 729amino acids and is 50% identical to human intestinal PEPT1.

Studies of PEPT1 and PEPT2 have shown that the transporters account forthe absorption and reabsorption of certain therapeutically activecompounds. The compounds include both biologically active peptides(e.g., renin inhibitors) and zwitterionic antibiotics. Based on theseobservations, researchers have suggested that peptide transporters, inconjunction with cytosolic peptidases, could be exploited for systemicdelivery of certain drugs in the form of peptide prodrugs (see Tsuji andTamai, Pharm. Res. 1996, 13, 963-977). Dipeptide analogues ofα-methyldopa, L-α-methyldopa-Phe and L-α-methyldopa-Pro, for example,are absorbed more efficiently in the intestine than α-methyldopa alone.Once across the intestinal membrane, the dipeptides are hydrolyzed bycytosolic peptidases to release α-methyldopa.

Gallop et al have provided evidence from transporter mRNA expressionprofiling studies that PEPT expression in rat and human extends broadlyover the length of the intestine, including the colon (U.S. PatentApplication Ser. No. 60/351,808 filed 24 Jan. 2002). They have suggestedthat sustained exposure to a substrate for a PEPT transporter could beachieved by formulating such a compound in an extended-release dosageform, which would gradually release the compound during transit of theformulation through the large intestine.

Peptide prodrug derivatives of gabapentin and other GABA analog drugsare contemplated by Bryans et al (see International Application No. WO01/90052; U.K. Application GB 2,362,646; European Application EP1,178,034). These workers have disclosed gabapentin derivatives whereinthe amino group is blocked with particular α-aminoacyl or dipeptidemoieties. More specifically, the α-amino acids comprising these peptideprodrug derivatives are the 20 naturally encoded α-amino acids, plusphenylglycine.

Prodrug derivatives of gabapentin and other GABA analog drugs are alsodisclosed by Gallop et al (see the co-pending International ApplicationsWO 02/28881, WO 02/28883, WO 02/28411 and WO 02/32376). The compoundsdisclosed therein are bile acid conjugates of GABA analogs that aredesigned to be actively transported across the intestinal mucosa viainteraction with the ileal bile acid transporter. These conjugates arefurther designed to undergo enterohepatic recirculation and to slowlyrelease the parent GABA analog into the systemic circulation. Additionalprodrug derivatives of gabapentin and other GABA analog drugs aredisclosed by Gallop et al (see the co-pending International ApplicationWO 02/42414). The compounds disclosed therein are α-aminoacyl andβ-aminoacyl conjugates of GABA analogs that are designed to be activelyabsorbed across the intestinal mucosa via interaction with peptidetransporters expressed in the intestine.

SUMMARY OF THE INVENTION

This invention is directed to the surprising discovery that PEPT1 andPEPT2 oligopeptide transporters can be utilized to provide sustainedsystemic concentrations of drugs administered to an animal. Thisinvention, therefore, permits sustained therapeutic or prophylacticsystemic blood concentrations of GABA analogues which heretofore couldnot be achieved. The present invention addresses the deficiencies ofknown GABA analogs by providing prodrugs of GABA analogs, andcompositions of prodrugs of GABA analogs and methods for making prodrugsof GABA analogs. The present invention also provides methods for usingprodrugs of GABA analogs and methods for using compositions of prodrugsof GABA analogs for treating or preventing common diseases and/ordisorders. The prodrugs of the present invention are substrates forpeptide transporters (PEPT1 and/or PEPT2) expressed in the mammaliangastrointestinal tract. This invention also provides sustained releasedosage formulations containing prodrugs of GABA analogs that aresubstrates for peptide transporters, and the use of such formulations tominimize the frequency of dosing necessary to treat patients in need ofGABA analog therapy.

Accordingly, in one of its aspects, this invention is directed to acompound of Formula (I):

H—I_(i)-J_(j)-D-K_(k)—OH  (1)

wherein:

H is hydrogen;

I is —[NR⁵⁰—(CR⁵¹R⁵²)_(a)—(CR⁵³R⁵⁴)_(b)—C(O)]—;

J is —[NR⁵⁵—(CR⁵⁶R⁵⁷)_(c)—(CR⁵⁸R⁵⁹)_(d)—C(O)]—;

K is —[NR⁶⁰—(CR⁶¹R⁶²)_(e)—(CR⁶³R⁶⁴)_(f)—C(O)]—;

wherein a, b, c, d, e and f are independently 0 or 1, provided that atleast one of a and b is 1, at least one of c and d is 1, and at leastone of e and f is 1;

and wherein i, j and k are independently 0 or 1, provided that at leastone of i, j and k is 1;

D is a moiety derived from a GABA analog having the following structure:

wherein:

R³ is a covalent bond linking the GABA analog moiety to J_(j);

R⁴ is hydrogen, or R⁴ and R⁹ together with the atoms to which they areattached form an azetidine, substituted azetidine, pyrrolidine orsubstituted pyrrolidine ring;

R⁵ and R⁶ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl;

R⁷ and R⁸ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, aryl, substitutedaryl, heteroaryl and substituted heteroaryl, or R⁷ and R⁸ together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclic or substituted heterocyclic ring;

R⁹ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryl andsubstituted heteroaryl;

R¹⁰ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryland substituted heteroaryl;

R¹¹ is C(O)R¹², wherein R¹² is a covalent bond linking the GABA analogmoiety to K_(k);

R⁵⁰ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl orR⁵⁰ and R⁵¹ together with the atoms to which they are attached form aheterocyclyl ring;

R⁵¹ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁵¹ and R⁵² together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁵¹ andR⁵³ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

R⁵² is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl;

R⁵³ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁵³ and R⁵⁴ together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

R⁵⁴ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl;

R⁵⁵ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl orR⁵⁵ and R⁵⁶, together with the atoms to which they are attached form aheterocyclyl ring;

R⁵⁶ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁵⁶ and R⁵⁷ together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁵⁶ andR⁵⁸ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

R⁵⁷ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl;

R⁵⁸ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁵⁸ and R⁵⁹ together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

R⁵⁹ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl;

R⁶⁰ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl orR⁶⁰ and R⁶¹, together with the atoms to which they are attached form aheterocyclyl ring;

R⁶¹ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁶¹ and R⁶² together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁶¹ andR⁶³ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

R⁶² is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl;

R⁶³ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁶³ and R⁶⁴ together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

R⁶⁴ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl;

and pharmaceutically acceptable salts, hydrates and solvates thereof,

provided that if k is 0 then neither I nor J is derived from alanine,arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid,glycine, histidine, isoleucine, leucine, lysine, methionine,phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valineor phenylglycine;

and provided that when R⁵, R⁶, R⁹ and R¹⁰ are each hydrogen, then R⁷ andR⁸ are neither both hydrogen nor both methyl;

and yet further provided that when D is either of the following moieties

neither I nor J are selected from a group of moieties selected from thefollowing moieties: H₂NCH₂C(O)—, H₂NCH(CH₃)C(O)—, NH₂CH₂CH₂C(O)— and

In a preferred embodiment, the compound of Formula (I) is sufficientlystable such that less than 50% of the compound is metabolized afterincubation in vitro with Caco-2 homogenate for 1 hour, as described inmore detail in Example 6.

In another aspect, this invention is directed to a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof Formula (I) and a pharmaceutically acceptable carrier. Thepharmaceutical composition may be used to treat or prevent epilepsy,depression, anxiety, psychosis, faintness attacks, hypokinesia, cranialdisorders, neurodegenerative disorders, panic, pain (especiallyneuropathic pain, muscular pain or skeletal pain), inflammatory disease,insomnia, gastrointestinal disorders or ethanol withdrawal syndrome in apatient.

In another aspect, this invention is directed to sustained release oraldosage forms comprising a therapeutically effective amount of a compoundof Formula (I) and, optionally, a pharmaceutically acceptable carrier.

In another aspect, this invention is directed to a method for treatingor preventing epilepsy, depression, anxiety, psychosis, faintnessattacks, hypokinesia, cranial disorders, neurodegenerative disorders,panic, pain (especially neuropathic pain, muscular pain or skeletalpain), inflammatory disease, insomnia, gastrointestinal disorders orethanol withdrawal syndrome in a patient. The method comprisesadministering to a patient in need of such therapy a therapeuticallyeffective amount of a compound of Formula (I), optionally with apharmaceutically acceptable carrier.

In another aspect, this invention is directed to a method for achievingsustained release of a GABA analog in a patient in need of therapy. Themethod comprises orally administering to the patient a sustained releasedosage form containing a therapeutically effective amount of a compoundof Formula (I), and optionally, a pharmaceutically acceptable carrier.

In yet another aspect, this invention is directed to a method forachieving improved dose-proportional exposure of a GABA analog in apatient, said method comprising orally administering to the patient atherapeutically effective amount of a compound of Formula (I) and,optionally, a pharmaceutically acceptable carrier.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the synthesis of aminoacyl and other peptidederivatives of GABA analogs.

FIG. 2 illustrates the synthesis of L-Aspartyl-Gabapentin derivatives.

FIG. 3 illustrates the synthesis of L-Tyrosine-Gabapentin derivatives.

DETAILED DESCRIPTION OF THE INVENTION

This invention is directed to compounds that provide for sustainedsystemic concentrations of GABA analogues or active metabolites thereoffollowing administration to animals. This invention is also directed tomethods using the compounds and pharmaceutical compositions that areused in such methods. However, prior to describing this invention infurther detail, the following terms will first be defined:

DEFINITIONS

As used herein, the term “animal” refers to various species such asmammalian and avian species including, by way of example, humans,cattle, sheep, horses, dogs, cats, turkeys, chicken, and the like.Preferably, the animal is a mammal and even more preferably is a human.

“Administering to the animal” refers to delivering a compound of Formula(I) to an animal through a suitable route. Such routes include, forexample, oral, rectal, subcutaneous, intravenous, intramuscular andintranasal. Preferably, the compound is orally administered to theanimal.

“Orally delivered” and “orally administered” refer to compounds,compositions and/or dosage forms which are administered to an animal inan oral form, preferably, in a pharmaceutically acceptable diluent. Oraldelivery includes ingestion of the compounds, compositions and/or dosageforms, as well as oral gavage of the compounds and compositions.

“PEPT1 oligopeptide transporter” refers to a type of protein thatabsorbs peptides in certain tissues, such as the intestine. Thistransporter is described and characterized in the literature. See Adibi,S. A., Gastroenterology 1997, 113, 332-340 and Leibach et al., Ann. Rev.Nutr. 1996, 16, 99-119 for a discussion of the transporter.

“PEPT2 oligopeptide transporter” refers to a type of protein thatabsorbs peptides in certain tissues, such as the kidney. Thistransporter is described and characterized in the literature. See Dieck,S. T. et al., GLIA 1999, 25, 10-20, Leibach et al., Ann. Rev. Nutr.1996, 16, 99-119; and Wong et al., Am. J. Physiol. 1998, 275, C967-C975for a discussion of the transporter.

“Transported by either a PEPT1 or PEPT2 oligopeptide transporter” refersto the translocation of a molecule across a membrane of a cellexpressing the transporter. The translocation occurs through interactionwith the transporter and is energized by cotransport of H⁺ ions acrossthe membrane.

“Amino acid” is intended to denote α-amino acids and β-amino acids only.

α-Amino acids are molecules of the formula:

HNR⁵⁰CR⁵¹R⁵²—C(O)OH:

wherein:

R⁵⁰ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl orR⁵⁰ and R⁵¹ together with the atoms to which they are attached form aheterocyclyl ring;

R⁵¹ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁵¹ and R⁵² together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

R⁵² is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl.

β-Amino acids are molecules of formula:

HNR⁵⁰—(CR⁵¹R⁵²)—(CR⁵³R⁵⁴)—C(O)OH:

wherein:

R⁵⁰ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl orR⁵⁰ and R⁵¹ together with the atoms to which they are attached form aheterocyclyl ring;

R⁵¹ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁵¹ and R⁵² together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁵¹ andR⁵³ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

R⁵² is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl;

R⁵³ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁵³ and R⁵⁴ together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

R⁵⁴ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl.

“Naturally occurring amino acid” refers to any of the alpha-amino acidsthat are the chief components of proteins. The amino acids are eithersynthesized by living cells or are obtained as essential components ofthe diet. Such amino acids include, for example, the following: alanine,arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid,glycine, histidine, isoleucine, leucine, lysine, methionine,phenylalanine, proline, serine, threonine, tryptophan, tyrosine andvaline.

“Derived from a compound” refers to a moiety that is structurallyrelated to such a compound. The structure of the moiety is identical tothe compound except at 1 or 2 positions. At these positions, either ahydrogen atom attached to a heteroatom or a hydroxyl moiety of acarboxylic acid group has been replaced with a covalent bond that servesas a point of attachment to another moiety. “Derived from an α-aminoacid” is meant to specifically denote that the point of attachment iseither the terminal α-amino group or the terminal α-acid group of theamino acid. For example, the moiety —NHCH₂C(O)— is derived from glycine.In the moiety, both a hydrogen atom on the amino group and a hydroxylportion of the carboxyl group have been replaced with a covalent bond.

“GABA analog” refers to a compound of the following structure:

wherein

R⁴ is hydrogen, or R⁴ and R⁹ together with the atoms to which they areattached form an azetidine, substituted azetidine, pyrrolidine orsubstituted pyrrolidine ring;

R⁵ and R⁶ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl;

R⁷ and R⁸ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, aryl, substitutedaryl, heteroaryl and substituted heteroaryl, or R⁷ and R⁸ together withthe atoms to which they are attached form a cycloalkyl substitutedcycloalkyl, heterocyclic or substituted heterocyclic ring;

R⁹ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryl andsubstituted heteroaryl; and,

R¹⁰ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryland substituted heteroaryl.

“Active metabolite of a drug” refers to products of in vivo modificationof the drug which have therapeutic or prophylactic effect.

“Therapeutic or prophylactic blood concentrations” refers to systemicexposure to a sufficient concentration of a drug or an active metabolitethereof over a sufficient period of time to effect disease therapy or toprevent the onset or reduce the severity of a disease in the treatedanimal.

“Sustained release” refers to release of a drug or an active metabolitethereof into the systemic circulation over a prolonged period of time(typically periods of at least six hours) relative to that achieved byadministration of a conventional immediate-release formulation of thedrug.

“Conjugating” refers to the formation of a covalent bond.

“Active transport or active transport mechanism” refers to the movementof molecules across cellular membranes that: a) is directly orindirectly dependent on an energy mediated process (i.e. driven by ATPhydrolysis, ion gradient, etc); or b) occurs by facilitated diffusionmediated by interaction with specific transporter proteins; or c) occursthrough a modulated solute channel.

“Amino-protecting group” or “amino-blocking group” refers to any groupwhich when bound to one or more amino groups prevents reactions fromoccurring at these amino groups and which protecting groups can beremoved by conventional chemical steps to reestablish the amino group.The particular removable blocking group is not critical and preferredamino blocking groups include, by way of example only, t-butyoxycarbonyl(t-BOC), benzyloxycarbonyl (CBZ), and the like.

“Carboxyl-protecting group” or “carboxyl-blocking group” refers to anygroup which when bound to one or more carboxyl groups prevents reactionsfrom occurring at these groups and which protecting groups can beremoved by conventional chemical steps to reestablish the carboxylgroup. The particular removable blocking group is not critical andpreferred carboxyl blocking groups include, by way of example only,esters of the formula —COOR″ where R″ is selected from the groupconsisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl,aryl, substituted aryl, alkaryl, substituted alkaryl, cycloalkyl,substituted cycloalkyl, heteroaryl, substituted heteroaryl,heterocyclic, and substituted heterocyclic.

“AUC” is the area under the plasma drug concentration-versus-time curveextrapolated from zero time to infinity.

“C_(max)” is the highest drug concentration observed in plasma followingan extravascular dose of drug.

“Prodrug” refers to a derivative of a drug molecule that requires atransformation within the body to release the active drug. Prodrugs arefrequently (though not necessarily) pharmacologically inactive untilconverted to the parent drug. Typically, prodrugs are designed toovercome pharmaceutical and/or pharmacokinetically based problemsassociated with the parent drug molecule that would otherwise limit theclinical usefulness of the drug.

“Promoiety” refers to a form of protecting group that when used to maska functional group within a drug molecule converts the drug into aprodrug. Typically, the promoiety will be attached to the drug viabond(s) that are cleaved by enzymatic or non-enzymatic means in vivo.Ideally, the promoiety is rapidly cleared from the body upon cleavagefrom the prodrug.

“Dose-Proportional Drug Exposure” or “Dose-Proportionality” refers tothe situation where either (i) the concentration of a drug in the plasmaof an animal over time (at a therapeutically relevant level) provides acurve of concentration of the drug in the plasma over time, the curvehaving an area under the curve (AUC) which is substantially proportionalto the dose of the drug administered; or (ii) the concentration of adrug in the plasma of an animal over time (at a therapeutically relevantlevel) provides a curve of concentration of the drug in the plasma overtime, the curve having a maximum plasma concentration (C_(max)) which issubstantially proportional to the dose of GABA analog administered.

“Alkyl” refers to alkyl groups preferably having from 1 to 20 carbonatoms and more preferably 1 to 6 carbon atoms. This term is exemplifiedby groups such as methyl, t-butyl, n-heptyl, octyl, dodecyl and thelike.

“Substituted alkyl” refers to an alkyl group, preferably of from 1 to 20carbon atoms, having from 1 to 5 substituents selected from the groupconsisting of alkoxy, substituted alkoxy, acyl, acylamino,thiocarbonylamino, acyloxy, amino, amidino, alkyl amidino, thioamidino,aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy,aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxylaryl,substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, carboxyl,carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl,carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substitutedaryl, carboxylheteroaryl, carboxyl-substituted heteroaryl,carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl,substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl,substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl,substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl,thioheterocyclic, substituted thioheterocyclic, heteroaryl, substitutedaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic,cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substitutedheteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,oxycarbonylamino, oxythiocarbonylamino, —OS(O)₂-alkyl,—OS(O)₂-substituted alkyl, —OS(O)₂-aryl, —OS(O)₂-substituted aryl,—OS(O)₂-heteroaryl, —OS(O)₂-substituted heteroaryl,—OS(O)₂-heterocyclic, —OS(O)₂-substituted heterocyclic, —OSO₂—NRR whereR is hydrogen or alkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl,—NRS(O)₂-aryl, —NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl,—NRS(O)₂-substituted heteroaryl, —NRS(O)₂-heterocyclic,—NRS(O)₂-substituted heterocyclic, —NRS(O)₂—NR-alkyl,—NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl, —NRS(O)₂—NR-substitutedaryl, —NRS(O)₂—NR-heteroaryl, —NRS(O)₂—NR-substituted heteroaryl,—NRS(O)₂—NR-heterocyclic, —NRS(O)₂—NR-substituted heterocyclic where Ris hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substitutedalkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino,mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino,mono- and di-heterocyclic amino, mono- and di-substituted heterocyclicamino, unsymmetric di-substituted amines having different substituentsselected from the group consisting of alkyl, substituted alkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic and substituted alkyl groups having aminogroups blocked by conventional blocking groups such as Boc, Cbz, formyl,and the like or alkyl/substituted alkyl groups substituted with—SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substitutedalkenyl, —SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

“Alkoxy” refers to the group “alkyl-O—” which includes, by way ofexample, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy,sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.

“Substituted alkoxy” refers to the group “substituted alkyl-O—”.

“Acyl” refers to the groups H—C(O)—, alkyl-C(O)—, substitutedalkyl-C(O)—, alkenyl-C(O)—, substituted alkenyl-C(O)—, alkynyl-C(O)—,substituted alkynyl-C(O)— cycloalkyl-C(O), substituted cycloalkyl-C(O)—,aryl-C(O)—, substituted aryl-C(O)—, heteroaryl-C(O)—, substitutedheteroaryl-C(O), heterocyclic-C(O)—, and substituted heterocyclic-C(O)—wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

“Acylamino” refers to the group —C(O)NRR where each R is independentlyselected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl,substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl,substituted heteroaryl, heterocyclic, substituted heterocyclic and whereeach R is joined to form together with the nitrogen atom a heterocyclicor substituted heterocyclic ring wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Thiocarbonylamino” refers to the group —C(S)NRR where each R isindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic and where each R is joined to form, together with thenitrogen atom a heterocyclic or substituted heterocyclic ring whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

“Acyloxy” refers to the groups alkyl-C(O)O—, substituted alkyl-C(O)O—,alkenyl-C(O)O—, substituted alkenyl-C(O)O—, alkynyl-C(O)O—, substitutedalkynyl-C(O)O—, aryl-C(O)O—, substituted aryl-C(O)O—, cycloalkyl-C(O)O—,substituted cycloalkyl-C(O)O—, heteroaryl-C(O)O—, substitutedheteroaryl-C(O)O—, heterocyclic-C(O)O—, and substitutedheterocyclic-C(O)O— wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Alkenyl” refers to alkenyl group preferably having from 2 to 20 carbonatoms and more preferably 2 to 6 carbon atoms and having at least 1 andpreferably from 1-2 sites of alkenyl unsaturation.

“Substituted alkenyl” refers to alkenyl groups having from 1 to 5substituents selected from the group consisting of alkoxy, substitutedalkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino,alkylamidino, thioamidino, aminoacyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl,aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl,halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl,carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substitutedcycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl,carboxyl-substituted heteroaryl, carboxylheterocyclic,carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl,thioaryl, substituted thioaryl, thiocycloalkyl, substitutedthiocycloalkyl, thioheteroaryl, substituted thioheteroaryl,thioheterocyclic, substituted thioheterocyclic, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —OS(O)₂-alkyl, —OS(O)₂-substituted alkyl,—OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic and substituted alkenyl groups having amino groups blockedby conventional blocking groups such as Boc, Cbz, formyl, and the likeor alkenyl/substituted alkenyl groups substituted with —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl,—SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

“Alkenyloxy” refers to the group —O-alkenyl.

“Substituted alkenyloxy” refers to the group —O-substituted alkenyloxy.

“Alkynyl” refers to alkynyl group preferably having from 2 to 20 carbonatoms and more preferably 3 to 6 carbon atoms and having at least 1 andpreferably from 1-2 sites of alkynyl unsaturation.

“Substituted alkynyl” refers to alkynyl groups having from 1 to 5substituents selected from the group consisting of alkoxy, substitutedalkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino,alkylamidino, thioamidino, aminoacyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl,aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl,halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl,carboxyl-substituted alkyl, carboxyl-cylcoalkyl, carboxyl-substitutedcycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl,carboxyl-substituted heteroaryl, carboxylheterocyclic,carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl,thioaryl, substituted thioaryl, thiocycloalkyl, substitutedthiocycloalkyl, thioheteroaryl, substituted thioheteroaryl,thioheterocyclic, substituted thioheterocyclic, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —OS(O)₂-alkyl, —OS(O)₂-substituted alkyl,—OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic and substituted alkynyl groups having amino groups blockedby conventional blocking groups such as Boc, Cbz, formyl, and the likeor alkynyl/substituted alkynyl groups substituted with —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl,—SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

“Alkylene” refers to a divalent alkylene group preferably having from 1to 20 carbon atoms and more preferably 1 to 6 carbon atoms. This term isexemplified by groups such as methylene (—CH₂—), ethylene (—CH₂CH₂—),the propylene isomers (e.g., —CH₂CH₂CH₂— and —CH(CH₃)CH₂—) and the like.

“Substituted alkylene” refers to alkylene groups having from 1 to 5substituents selected from the group consisting of alkoxy, substitutedalkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino,alkylamidino, thioamidino, aminoacyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl,aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl,halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl,carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substitutedcycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl,carboxyl-substituted heteroaryl, carboxylheterocyclic,carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl,thioaryl, substituted thioaryl, thiocycloalkyl, substitutedthiocycloalkyl, thioheteroaryl, substituted thioheteroaryl,thioheterocyclic, substituted thioheterocyclic, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —OS(O)₂-alkyl, —OS(O)₂-substituted alkyl,—OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic and substituted alkenyl groups having amino groups blockedby conventional blocking groups such as Boc, Cbz, formyl, and the likeor alkenyl/substituted alkenyl groups substituted with —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl,—SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

“Alkenylene” refers to a divalent alkenylene group preferably havingfrom 2 to 20 carbon atoms and more preferably 1 to 6 carbon atoms andhaving from 1 to 2 sites of alkenyl unsaturation. This term isexemplified by groups such as ethenylene (—CH═CH—), propenylene(—CH₂CH═CH—), and the like.

“Substituted alkenylene” refers to alkenylene groups having from 1 to 5substituents selected from the group consisting of alkoxy, substitutedalkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino,alkylamidino, thioamidino, aminoacyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl,aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl,halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl,carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substitutedcycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl,carboxyl-substituted heteroaryl, carboxylheterocyclic,carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl,thioaryl, substituted thioaryl, thiocycloalkyl, substitutedthiocycloalkyl, thioheteroaryl, substituted thioheteroaryl,thioheterocyclic, substituted thioheterocyclic, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —OS(O)₂-alkyl, —OS(O)₂-substituted alkyl,—OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic and substituted alkenyl groups having amino groups blockedby conventional blocking groups such as Boc, Cbz, formyl, and the likeor alkenyl/substituted alkenyl groups substituted with —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl,—SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

“Alkynylene” refers to a divalent alkynylene group preferably havingfrom 2 to 20 carbon atoms and more preferably 1 to 6 carbon atoms andhaving from 1 to 2 sites of alkynyl unsaturation. This term isexemplified by groups such as ethynylene, propynylene and the like.

“Substituted alkylene” refers to alkynylene groups having from 1 to 5substituents selected from the group consisting of alkoxy, substitutedalkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino,alkylamidino, thioamidino, aminoacyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl,aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl,halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl,carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substitutedcycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl,carboxyl-substituted heteroaryl, carboxylheterocyclic,carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl,thioaryl, substituted thioaryl, thiocycloalkyl, substitutedthiocycloalkyl, thioheteroaryl, substituted thioheteroaryl,thioheterocyclic, substituted thioheterocyclic, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —OS(O)₂-alkyl, —OS(O)₂-substituted alkyl,—OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic and substituted alkenyl groups having amino groups blockedby conventional blocking groups such as Boc, Cbz, formyl, and the likeor alkenyl/substituted alkenyl groups substituted with —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl,—SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

“Amidino” refers to the group H₂NC(═NH)— and the term “alkylamidino”refers to compounds having 1 to 3 alkyl groups (e.g., alkylHNC(═NH)—).

“Thioamidino” refers to the group RSC(—NH)— where R is hydrogen oralkyl.

“Aminoacyl” refers to the groups —NRC(O)alkyl, —NRC(O) substitutedalkyl, —NRC(O)cycloalkyl, —NRC(O) substituted cycloalkyl,—NRC(O)alkenyl, —NRC(O) substituted alkenyl, —NRC(O)alkynyl, —NRC(O)substituted alkynyl, —NRC(O)aryl, —NRC(O) substituted aryl,—NRC(O)heteroaryl, —NRC(O) substituted heteroaryl, —NRC(O)heterocyclic,and —NRC(O) substituted heterocyclic where R is hydrogen or alkyl andwherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

“Aminocarbonyloxy” refers to the groups —NRC(O)O-alkyl,—NRC(O)O-substituted alkyl, —NRC(O)O-alkenyl, —NRC(O)O-substitutedalkenyl, —NRC(O)O-alkynyl, —NRC(O)O-substituted alkynyl,—NRC(O)O-cycloalkyl, —NRC(O)O-substituted cycloalkyl, —NRC(O)O-aryl,—NRC(O)O-substituted aryl, —NRC(O)O-heteroaryl, —NRC(O)O-substitutedheteroaryl, —NRC(O)O-heterocyclic, and —NRC(O)O-substituted heterocyclicwhere R is hydrogen or alkyl and wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Oxycarbonylamino” refers to the groups —OC(O)NH₂, —OC(O)NRR,—OC(O)NR-alkyl, —OC(O)NR-substituted alkyl, —OC(O)NR-alkenyl,—OC(O)NR-substituted alkenyl, —OC(O)NR-alkynyl, —OC(O)NR-substitutedalkynyl, —OC(O)NR-cycloalkyl, —OC(O)NR-substituted cycloalkyl,—OC(O)NR-aryl, —OC(O)NR-substituted aryl, —OC(O)NR-heteroaryl,—OC(O)NR-substituted heteroaryl, —OC(O)NR-heterocyclic, and—OC(O)NR-substituted heterocyclic where R is hydrogen, alkyl or whereeach R is joined to form, together with the nitrogen atom a heterocyclicor substituted heterocyclic ring and wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Oxythiocarbonylamino” refers to the groups —OC(S)NH₂, —OC(S)NRR,—OC(S)NR-alkyl, —OC(S)NR-substituted alkyl, —OC(S)NR-alkenyl,—OC(S)NR-substituted alkenyl, —OC(S)NR-alkynyl, —OC(S)NR-substitutedalkynyl, —OC(S)NR-cycloalkyl, —OC(S)NR-substituted cycloalkyl,—OC(S)NR-aryl, —OC(S)NR-substituted aryl, —OC(S)NR-heteroaryl,—OC(S)NR-substituted heteroaryl, —OC(S)NR-heterocyclic, and—OC(S)NR-substituted heterocyclic where R is hydrogen, alkyl or whereeach R is joined to form together with the nitrogen atom a heterocyclicor substituted heterocyclic ring and wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Aminocarbonylamino” refers to the groups —NRC(O)NRR, —NRC(O)NR-alkyl,—NRC(O)NR-substituted alkyl, —NRC(O)NR-alkenyl, —NRC(O)NR-substitutedalkenyl, —NRC(O)NR-alkynyl, —NRC(O)NR-substituted alkynyl,—NRC(O)NR-aryl, —NRC(O)NR-substituted aryl, —NRC(O)NR-cycloalkyl,—NRC(O)NR-substituted cycloalkyl, —NRC(O)NR-heteroaryl, and—NRC(O)NR-substituted heteroaryl, —NRC(O)NR-heterocyclic, and—NRC(O)NR-substituted heterocyclic where each R is independentlyhydrogen, alkyl or where each R is joined to form together with thenitrogen atom a heterocyclic or substituted heterocyclic ring as well aswhere one of the amino groups is blocked by conventional blocking groupssuch as Boc, Cbz, formyl, and the like and wherein alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic and substituted heterocyclic are asdefined herein.

“Aminothiocarbonylamino” refers to the groups —NRC(S)NRR,—NRC(S)NR-alkyl, —NRC(S)NR-substituted alkyl, —NRC(S)NR-alkenyl,—NRC(S)NR-substituted alkenyl, —NRC(S)NR-alkynyl, —NRC(S)NR-substitutedalkynyl, —NRC(S)NR-aryl, —NRC(S)NR-substituted aryl,—NRC(S)NR-cycloalkyl, —NRC(S)NR-substituted cycloalkyl,—NRC(S)NR-heteroaryl, and —NRC(S)NR-substituted heteroaryl,—NRC(S)NR-heterocyclic, and —NRC(S)NR-substituted heterocyclic whereeach R is independently hydrogen, alkyl or where each R is joined toform together with the nitrogen atom a heterocyclic or substitutedheterocyclic ring as well as where one of the amino groups is blocked byconventional blocking groups such as Boc, Cbz, formyl, and the like andwherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

“Aryl” or “Ar” refers to a monovalent unsaturated aromatic carbocyclicgroup of from 6 to 14 carbon atoms having a single ring (e.g., phenyl)or multiple condensed rings (e.g., naphthyl or anthryl) which condensedrings may or may not be aromatic (e.g., 2-benzoxazolinone,2H-1,4-benzoxazin-3(4H)-one-7-yl, and the like). Preferred aryls includephenyl and naphthyl.

“Substituted aryl” refers to aryl groups which are substituted with from1 to 3 substituents selected from the group consisting of hydroxy, acyl,acylamino, thiocarbonylamino, acyloxy, alkyl, substituted alkyl, alkoxy,substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, amidino, alkylamidino, thioamidino, amino, aminoacyl,aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aryl,substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substitutedcycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy,substituted heterocyclyloxy, carboxyl, carboxylalkyl,carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substitutedcycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl,carboxyl-substituted heteroaryl, carboxylheterocyclic,carboxyl-substituted heterocyclic, carboxylamido, cyano, thiol,thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl,thioheteroaryl, substituted thioheteroaryl, thiocycloalkyl, substitutedthiocycloalkyl, thioheterocyclic, substituted thioheterocyclic,cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, halo,nitro, heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy,substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,oxycarbonylamino, oxythiocarbonylamino, —S(O)₂-alkyl, —S(O)₂-substitutedalkyl, —S(O)₂-cycloalkyl, —S(O)₂-substituted cycloalkyl, —S(O)₂-alkenyl,—S(O)₂-substituted alkenyl, —S(O)₂-aryl, —S(O)₂-substituted aryl,—S(O)₂-heteroaryl, —S(O)₂-substituted heteroaryl, —S(O)₂-heterocyclic,—S(O)₂-substituted heterocyclic, —OS(O)₂-alkyl, —OS(O)₂-substitutedalkyl, —OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NR where R is hydrogen or alkyl,—NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic and amino groups on the substituted aryl blocked byconventional blocking groups such as Boc, Cbz, formyl, and the like orsubstituted with —SO₂NRR where R is hydrogen or alkyl.

“Arylene” refers to a divalent unsaturated aromatic carbocyclic group offrom 6 to 14 carbon atoms having a single ring (e.g., phenylene) ormultiple condensed rings (e.g., naphthylene or anthrylene) whichcondensed rings may or may not be aromatic. Preferred arylenes includephenylene and naphthylene.

Substituted arylene refers to arylene groups which are substituted withfrom 1 to 3 substituents selected from the group consisting of hydroxy,acyl, acylamino, thiocarbonylamino, acyloxy, alkyl, substituted alkyl,alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, amidino, alkylamidino, thioamidino, amino,aminoacyl, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino,aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, carboxyl, carboxylalkyl,carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substitutedcycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl,carboxyl-substituted heteroaryl, carboxylheterocyclic,carboxyl-substituted heterocyclic, carboxylamido, cyano, thiol,thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl,thioheteroaryl, substituted thioheteroaryl, thiocycloalkyl, substitutedthiocycloalkyl, thioheterocyclic, substituted thioheterocyclic,cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, halo,nitro, heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy,substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,oxycarbonylamino, oxythiocarbonylamino, —S(O)₂-alkyl, —S(O)₂-substitutedalkyl, —S(O)₂-cycloalkyl, —S(O)₂-substituted cycloalkyl, —S(O)₂-alkenyl,—S(O)₂-substituted alkenyl, —S(O)₂-aryl, —S(O)₂-substituted aryl,—S(O)₂-heteroaryl, —S(O)₂-substituted heteroaryl, —S(O)₂-heterocyclic,—S(O)₂-substituted heterocyclic, —OS(O)₂-alkyl, —OS(O)₂-substitutedalkyl, —OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddiarylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic and amino groups on the substituted aryl blocked byconventional blocking groups such as Boc, Cbz, formyl, and the like orsubstituted with —SO₂NRR where R is hydrogen or alkyl.

“Aryloxy” refers to the group aryl-O— which includes, by way of example,phenoxy, naphthoxy, and the like.

“Substituted aryloxy” refers to substituted aryl-O— groups.

“Aryloxyaryl” refers to the group -aryl-O-aryl.

“Substituted aryloxyaryl” refers to aryloxyaryl groups substituted withfrom 1 to 3 substituents on either or both aryl rings selected from thegroup consisting of hydroxy, acyl, acylamino, thiocarbonylamino,acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, amidino,alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy,aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl,aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy,heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substitutedheterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl,carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substitutedheteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic,carboxylamido, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl,substituted thioaryl, thioheteroaryl, substituted thioheteroaryl,thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic,substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, halo, nitro, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —S(O)₂-alkyl, —S(O)₂-substituted alkyl,—S(O)₂-cycloalkyl, —S(O)₂-substituted cycloalkyl, —S(O)₂-alkenyl,—S(O)₂-substituted alkenyl, —S(O)₂-aryl, —S(O)₂-substituted aryl,—S(O)₂-heteroaryl, —S(O)₂-substituted heteroaryl, —S(O)₂-heterocyclic,—S(O)₂-substituted heterocyclic, —OS(O)₂-alkyl, —OS(O)₂-substitutedalkyl, —OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic and amino groups on the substituted aryl blocked byconventional blocking groups such as Boc, Cbz, formyl, and the like orsubstituted with —SO₂NRR where R is hydrogen or alkyl.

“Cycloalkyl” refers to cyclic alkyl groups of from 3 to 10 carbon atomshaving a single cyclic ring including, by way of example, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl and the like. Thisdefinition also includes bridged groups such as bicyclo[2.2.1]heptaneand bicyclo[3.3.1]nonane.

“Cycloalkyloxy” refers to —O-cycloalkyl.

“Cycloalkenyl” refers to cyclic alkenyl groups of form 3 to 10 carbonatoms having a single cyclic ring.

“Cycloalkenyloxy” refers to —O-cycloalkenyl.

“Substituted cycloalkyl” and “substituted cycloalkenyl” refers to ancycloalkyl or cycloalkenyl group, preferably of from 3 to 10 carbonatoms, having from 1 to 5 substituents selected from the groupconsisting of oxo (═O), thioxo (═S), alkoxy, substituted alkoxy, acyl,acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino,thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy,aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro,carboxyl, carboxylalkyl, carboxyl-substituted alkyl,carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substitutedheteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic,cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol,thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl,thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substitutedthioheteroaryl, thioheterocyclic, substituted, thioheterocyclic,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy,substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,oxycarbonylamino, oxythiocarbonylamino, —OS(O)₂-alkyl,—OS(O)₂-substituted alkyl, —OS(O)₂-aryl, —OS(O)₂-substituted aryl,—OS(O)₂-heteroaryl, —OS(O)₂-substituted heteroaryl,—OS(O)₂-heterocyclic, —OS(O)₂-substituted heterocyclic, —OSO₂—NRR whereR is hydrogen or alkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl,—NRS(O)₂-aryl, —NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl,—NRS(O)₂-substituted heteroaryl, —NRS(O)₂-heterocyclic,—NRS(O)₂-substituted heterocyclic, —NRS(O)₂—NR-alkyl,—NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl, —NRS(O)₂—NR-substitutedaryl, —NRS(O)₂—NR-heteroaryl, —NRS(O)₂—NR-substituted heteroaryl,—NRS(O)₂—NR-heterocyclic, —NRS(O)₂—NR-substituted heterocyclic where Ris hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substitutedalkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino,mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino,mono- and di-heterocyclic amino, mono- and di-substituted heterocyclicamino, unsymmetric di-substituted amines having different substituentsselected from the group consisting of alkyl, substituted alkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic and substituted alkynyl groups having aminogroups blocked by conventional blocking, groups such as Boc, Cbz,formyl, and the like or alkynyl/substituted alkynyl groups substitutedwith —SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substitutedalkenyl, —SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

“Substituted cycloalkyloxy” and “substituted cycloalkenyloxy” refers to—O-substituted cycloalkyl and —O-substituted cycloalkenyloxyrespectively.

“Cycloalkylene” refers to divalent cyclic alkylene groups of from 3 to10 carbon atoms having a single cyclic ring including, by way ofexample, cyclopropylene, cyclobutylene, cyclopentylene, cyclooctyleneand the like.

“Cycloalkenylene” refers to a divalent cyclic alkenylene groups of from3 to 10 carbon atoms having a single cyclic ring.

“Substituted cycloalkylene” and “substituted cycloalkenylene” refers toa cycloalkylene or cycloalkenylene group, preferably of from 3 to 8carbon atoms, having from 1 to 5 substituents selected from the groupconsisting of oxo (═O), thioxo (═S), alkoxy, substituted alkoxy, acyl,acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino,thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy,aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro,carboxyl, carboxylalkyl, carboxyl-substituted alkyl,carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substitutedheteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic,cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol,thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl,thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substitutedthioheteroaryl, thioheterocyclic, substituted thioheterocyclic,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy,substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,oxycarbonylamino, oxythiocarbonylamino, —OS(O)₂-alkyl,—OS(O)₂-substituted alkyl, —OS(O)₂-aryl, —OS(O)₂-substituted aryl,—OS(O)₂-heteroaryl, —OS(O)₂-substituted heteroaryl,—OS(O)₂-heterocyclic, —OS(O)₂-substituted heterocyclic, —OSO₂—NRR whereR is hydrogen or alkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl,—NRS(O)₂-aryl, —NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl,—NRS(O)₂-substituted heteroaryl, —NRS(O)₂-heterocyclic,—NRS(O)₂-substituted heterocyclic, —NRS(O)₂—NR-alkyl,—NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl, —NRS(O)₂—NR-substitutedaryl, —NRS(O)₂—NR-heteroaryl, —NRS(O)₂—NR-substituted heteroaryl,—NRS(O)₂—NR-heterocyclic, —NRS(O)₂—NR-substituted heterocyclic where Ris hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substitutedalkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino,mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino,mono- and di-heterocyclic amino, mono- and di-substituted heterocyclicamino, unsymmetric di-substituted amines having different substituentsselected from the group consisting of alkyl, substituted alkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic and substituted alkynyl groups having aminogroups blocked by conventional blocking groups such as Boc, Cbz, formyl,and the like or alkynyl/substituted alkynyl groups substituted withSO₂-alkyl, —SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substitutedalkenyl, —SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

“Cycloalkoxy” refers to —O-cycloalkyl groups.

“Substituted cycloalkoxy” refers to —O-substituted cycloalkyl groups.

“Guanidino” refers to the groups —NRC(═NR)NRR, —NRC(═NR)NR-alkyl,—NRC(═NR)NR-substituted alkyl, —NRC(═NR)NR-alkenyl,—NRC(═NR)NR-substituted alkenyl, —NRC(═NR)NR-alkynyl,—NRC(═NR)NR-substituted alkynyl, —NRC(═NR)NR-aryl,—NRC(═NR)NR-substituted aryl, —NRC(═NR)NR-cycloalkyl,—NRC(═NR)NR-heteroaryl, —NRC(═NR)NR-substituted heteroaryl,—NRC(═NR)NR-heterocyclic, and —NRC(═NR)NR-substituted heterocyclic whereeach R is independently hydrogen and alkyl as well as where one of theamino groups is blocked by conventional blocking groups such as Boc,Cbz, formyl, and the like and wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“N,N-Dimethylcarbamyloxy” refers to the group —OC(O)N(CH₃)₂.

“Guanidinosulfone” refers to the groups —NRC(═NR)NRSO₂-alkyl,—NRC(═NR)NRSO₂-substituted alkyl, —NRC(═NR)NRSO₂-alkenyl,—NRC(═NR)NRSO₂-substituted alkenyl, —NRC(═NR)NRSO₂-alkynyl,—NRC(═NR)NRSO₂-substituted alkynyl, —NRC(═NR)NRSO₂-aryl,—NRC(═NR)NRSO₂-substituted aryl, —NRC(═NR)NRSO₂-cycloalkyl,—NRC(═NR)NRSO₂-substituted cycloalkyl, —NRC(═NR)NRSO₂-heteroaryl, and—NRC(═NR)NRSO₂-substituted heteroaryl, —NRC(═NR)NRSO₂-heterocyclic, and—NRC(═NR)NRSO₂-substituted heterocyclic where each R is independentlyhydrogen and alkyl and wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Halo” or “halogen” refers to fluoro, chloro, bromo and iodo andpreferably is either chloro or bromo.

“Heteroaryl” refers to an aromatic carbocyclic group of from 2 to 10carbon atoms and 1 to 4 heteroatoms selected from the group consistingof oxygen, nitrogen and sulfur within the ring. Such heteroaryl groupscan have a single ring (e.g., pyridyl or furyl) or multiple condensedrings (e.g., indolizinyl or benzothienyl). Preferred heteroaryls includepyridyl, pyrrolyl, indolyl and furyl.

“Substituted heteroaryl” refers to heteroaryl groups which aresubstituted with from 1 to 3 substituents selected from the groupconsisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy,alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, amidino,alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy,aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl,aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy,heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substitutedheterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl,carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substitutedheteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic,carboxylamido, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl,substituted thioaryl, thioheteroaryl, substituted thioheteroaryl,thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic,substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, halo, nitro, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —S(O)₂-alkyl, —S(O)₂-substituted alkyl,—S(O)₂-cycloalkyl, —S(O)₂-substituted cycloalkyl, —S(O)₂-alkenyl,—S(O)₂-substituted alkenyl, —S(O)₂-aryl, —S(O)₂-substituted aryl,—S(O)₂-heteroaryl, —S(O)₂-substituted heteroaryl, —S(O)₂-heterocyclic,—S(O)₂-substituted heterocyclic, —OS(O)₂-alkyl, —OS(O)₂-substitutedalkyl, —OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic and amino groups on the substituted aryl blocked byconventional blocking groups such as Boc, Cbz, formyl, and the like orsubstituted with —SO₂NRR where R is hydrogen or alkyl.

“Heteroarylene” refers to a divalent aromatic carbocyclic group of from2 to 10 carbon atoms and 1 to 4 heteroatoms selected from the groupconsisting of oxygen, nitrogen and sulfur within the ring. Suchheteroarylene groups can have a single ring (e.g., pyridylene orfurylene) or multiple condensed rings (e.g., indolizinylene orbenzothienylene). Preferred heteroarylenes include pyridylene,pyrrolylene, indolylene and furylene.

“Substituted heteroarylene” refers to heteroarylene groups which aresubstituted with from 1 to 3 substituents selected from the groupconsisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy,alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, amidino,alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy,aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl,aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy,heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substitutedheterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl,carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substitutedheteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic,carboxylamido, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl,substituted thioaryl, thioheteroaryl, substituted thioheteroaryl,thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic,substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, halo, nitro, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —S(O)₂-alkyl, —S(O)₂-substituted alkyl,—S(O)₂-cycloalkyl, —S(O)₂-substituted cycloalkyl, —S(O)₂-alkenyl,—S(O)₂-substituted alkenyl, —S(O)₂-aryl, —S(O)₂-substituted aryl,—S(O)₂-heteroaryl, —S(O)₂-substituted heteroaryl, —S(O)₂-heterocyclic,—S(O)₂-substituted heterocyclic, —OS(O)₂-alkyl, —OS(O)₂-substitutedalkyl, —OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic and amino groups on the substituted aryl blocked byconventional blocking groups such as Boc, Cbz, formyl, and the like orsubstituted with —SO₂NRR where R is hydrogen or alkyl.

“Heteroaryloxy” refers to the group —O-heteroaryl and “substitutedheteroaryloxy” refers to the group —O-substituted heteroaryl.

“Heterocycle” or “heterocyclic” refers to a saturated or unsaturatedgroup having a single ring or multiple condensed rings, from 1 to 10carbon atoms and from 1 to 4 hetero atoms selected from the groupconsisting of nitrogen, sulfur or oxygen within the ring wherein, infused ring systems, one or more the rings can be aryl or heteroaryl.

“Substituted heterocyclic” refers to heterocycle groups which aresubstituted with from 1 to 3 substituents selected from the groupconsisting of oxo (═O), thioxo (═S), alkoxy, substituted alkoxy, acyl,acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino,thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy,aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro,carboxyl, carboxylalkyl, carboxyl-substituted alkyl,carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substitutedheteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic,cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol,thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl,thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substitutedthioheteroaryl, thioheterocyclic, substituted thioheterocyclic,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy,substituted heteroaryloxy, —C(O)O-aryl, —C(O)O-substituted aryl,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —OS(O)₂-alkyl, —OS(O)₂-substituted alkyl,—OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic and substituted alkynyl groups having amino groups blockedby conventional blocking groups such as Boc, Cbz, formyl, and the likeor alkynyl/substituted alkynyl groups substituted with —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl,—SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

Examples of heterocycles and heteroaryls include, but are not limitedto, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole,indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine,naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine,carbazole, carboline, phenanthridine, acridine, phenanthroline,isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine,imidazolidine, imidazoline, piperidine, piperazine, indoline,phthalimide, 1,2,3,4-tetrahydroisoquinoline,4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene,benzo[b]thiophene, morpholinyl, thiomorpholinyl (also referred to asthiamorpholinyl), piperidinyl, pyrrolidine, tetrahydrofuranyl, and thelike.

“Heterocyclene” refers to a divalent saturated or unsaturated grouphaving a single ring or multiple condensed rings, from 1 to 10 carbonatoms and from 1 to 4 hetero atoms selected from the group consisting ofnitrogen, sulfur or oxygen within the ring wherein, in fused ringsystems, one or more the rings can be aryl or heteroaryl.

“Substituted heterocyclene” refers to heterocyclene groups which aresubstituted with from 1 to 3 substituents selected from the groupconsisting of oxo (═O), thioxo (═S), alkoxy, substituted alkoxy, acyl,acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino,thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy,aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro,carboxyl, carboxylalkyl, carboxyl-substituted alkyl,carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substitutedheteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic,cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol,thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl,thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substitutedthioheteroaryl, thioheterocyclic, substituted thioheterocyclic,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy,substituted heteroaryloxy, —C(O)O-aryl, —C(O)O-substituted aryl,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —OS(O)₂-alkyl, —OS(O)₂-substituted alkyl,—OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and dialkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic and substituted alkynyl groups having amino groups blockedby conventional blocking groups such as Boc, Cbz, formyl, and the likeor alkynyl/substituted alkynyl groups substituted with —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl,—SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

“Heterocyclyloxy” refers to the group —O-heterocyclic and “substitutedheterocyclyloxy” refers to the group —O-substituted heterocyclic.

“Thiol” refers to the group —SH.

“Thioalkyl” refers to the groups —S-alkyl.

“Substituted thioalkyl” refers to the group —S-substituted alkyl.

“Thiocycloalkyl” refers to the groups —S-cycloalkyl.

“Substituted thiocycloalkyl” refers to the group —S-substitutedcycloalkyl.

“Thioaryl” refers to the group —S-aryl and “substituted thioaryl” refersto the group —S-substituted aryl.

“Thioheteroaryl” refers to the group —S-heteroaryl and “substitutedthioheteroaryl” refers to the group —S-substituted heteroaryl.

“Thioheterocyclic” refers to the group —S-heterocyclic and “substitutedthioheterocyclic” refers to the group —S-substituted heterocyclic.

“Amino” refers to the —NH₂ group.

“Substituted amino” refers to the —NR′R″ group wherein R′ and R″ areindependently hydrogen, alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic or where R′ and R″,together with the nitrogen atom pendent thereto, form a heterocyclicring.

“Pharmaceutically acceptable salt” refers to pharmaceutically acceptablesalts of a compound of Formula (I), which salts are derived from avariety of organic and inorganic counter ions well known in the art andinclude, by way of example only, sodium, potassium, calcium, magnesium,ammonium, tetraalkylammonium, and the like; and when the moleculecontains a basic functionality, salts of organic or inorganic acids,such as hydrochloride, hydrobromide, tartrate, mesylate, acetate,maleate, oxalate and the like.

“Pharmaceutically acceptable carrier” refers to a carrier that is usefulin preparing a pharmaceutical composition that is generally safe,non-toxic and neither biologically nor otherwise undesirable, andincludes a carrier that is acceptable for veterinary use as well ashuman pharmaceutical use. “A pharmaceutically acceptable carrier” asused in the specification and claims includes both one and more than onesuch carrier.

“Treating” or “treatment” of a disease includes:

(1) preventing the disease, i.e. causing the clinical symptoms of thedisease not to develop in a mammal that may be exposed to or predisposedto the disease but does not yet experience or display symptoms of thedisease,

(2) inhibiting the disease, i.e., arresting or reducing the developmentof the disease or its clinical symptoms, or

(3) relieving the disease, i.e., causing regression of the disease orits clinical symptoms.

A “therapeutically effective amount” means the amount of a compoundthat, when administered to a mammal for treating a disease, issufficient to effect such treatment for the disease. The“therapeutically effective amount” will vary depending on the compound,the disease and its severity and the age, weight, etc., of the mammal tobe treated.

Utility

The compounds and methods described herein provide for the sustainedrelease of the GABA analog or active metabolite thereof relative todosing with the parent drug itself. For example, a compound and/orcomposition of the invention is administered to a patient, preferably ahuman, suffering from epilepsy, depression, anxiety, psychosis,faintness attacks, hypokinesia, cranial disorders, neurodegenerativedisorders, panic, pain (especially, neuropathic pain and muscular andskeletal pain), inflammatory disease (i.e., arthritis), insomnia,gastrointestinal disorders or ethanol withdrawal syndrome. Further, incertain embodiments, the compounds and/or compositions of the inventionare administered to a patient, preferably a human, as a preventativemeasure against various diseases or disorders. Thus, the compoundsand/or compositions of the invention may be administered as apreventative measure to a patient having a predisposition for epilepsy,depression, anxiety, psychosis, faintness attacks, hypokinesia, cranialdisorders, neurodegenerative disorders, panic, pain (especiallyneuropathic pain and muscular and skeletal pain), inflammatory disease(i.e., arthritis), insomnia, gastrointestinal disorders and ethanolwithdrawal syndrome. Accordingly, the compounds and/or compositions ofthe invention may be used for the prevention of one disease or disorderand concurrently treating another (e.g., prevention of psychosis whiletreating gastrointestinal disorders; prevention of neuropathic painwhile treating ethanol withdrawal syndrome).

The suitability of the compounds and/or compositions of the invention intreating epilepsy, depression, anxiety, psychosis, faintness attacks,hypokinesia, cranial disorders, neurodegenerative disorders, panic, pain(especially neuropathic pain and muscular and skeletal pain),inflammatory disease (i.e., arthritis), insomnia, gastrointestinaldisorders and ethanol withdrawal syndrome may be determined by methodsdescribed in the art (See, e.g., Satzinger et al., U.S. Pat. No.4,024,175; Satzinger et al., U.S. Pat. No. 4,087,544; Woodhuff, U.S.Pat. No. 5,084,479; Silverman et al., U.S. Pat. No. 5,563,175; Singh,U.S. Pat. No. 6,001,876; Horwell et al., U.S. Pat. No. 6,020,370;Silverman et al., U.S. Pat. No. 6,028,214; Horwell et al., U.S. Pat. No.6,103,932; Silverman et al., U.S. Pat. No. 6,117,906; Silverman,International Application No. WO 92/09560; Silverman et al.,International Application No. WO 93/23383; Horwell et al., InternationalApplication No. WO 97/29101, Horwell et al., International ApplicationNo. WO 97/33858; Horwell et al., International Application No. WO97/33859; Bryans et al., International Application No. WO 98/17627;Guglietta et al., International Application No. WO 99/08671; Bryans etal, International Application No. WO 99/21824; Bryans et al,International Application No. WO 99/31057; Magnus-Miller et al.,International Application No. WO 99/37296; Bryans et al., InternationalApplication No. WO 99/31075; Bryans et al., International ApplicationNo. WO 99/61424; Pande, International Application No. WO 00/23067;Bryans, International Application No. WO 00/31020; Bryans et al.,International Application No. WO 00/50027; and Bryans et al,International Application No. WO 02/00209). Procedures for using thecompounds and/or compositions of the invention for treating epilepsy,depression, anxiety, psychosis, faintness attacks, hypokinesia, cranialdisorders, neurodegenerative disorders, panic, pain (especiallyneuropathic pain and muscular and skeletal pain), inflammatory disease(i.e., arthritis), insomnia, gastrointestinal disorders and ethanolwithdrawal syndrome have also been described in the art (see referencesabove). Thus, it is well with the capability of those of skill in theart to assay and use the compounds and/or of the invention to treatepilepsy, depression, anxiety, psychosis, faintness attacks,hypokinesia, cranial disorders, neurodegenerative disorders, panic, pain(especially, neuropathic pain and muscular and skeletal pain),inflammatory disease (i.e., arthritis), insomnia, gastrointestinaldisorders and ethanol withdrawal syndrome.

All of the amino acid linked drugs described herein can also be used asintermediates in order to couple them to bile acids as disclosedpreviously, as in U.S. Provisional Application No. 60/297,472; U.S.Provisional Application No. 60/249,804; and U.S. Provisional ApplicationNo. 60/297,594 (along with the counterpart PCT Applications WO02/28881;WO02/2883; and WO02/32376) show GABA analogs coupled to bile acidsthrough amino acid linkages. U.S. Provisional Application No. 60/297,654(with counterpart PCT Application WO02/28882) shows L-Dopa analogscoupled to bile acids through amino acid linkages. All of theseapplications are incorporated herein by reference in their entirety.

PREFERRED EMBODIMENTS

This invention facilitates sustained therapeutic or prophylacticsystemic blood concentrations of GABA analogues which heretofore couldnot be achieved.

Accordingly, in one of its compound aspects, this invention is directedto a compound of Formula (I):

H—I_(i)-J_(j)-D-K_(k)—OH  (I)

wherein:

H is hydrogen;

I is —[NR⁵⁰—(CR⁵¹R⁵²)_(a)—(CR⁵³R⁵⁴)_(b)—C(O)]—;

J is [NR⁵⁵—(CR⁵⁶R⁵⁷)C—(CR⁵⁸R⁵⁹)_(d)—C(O)]—;

K is —[NR⁶⁰—(CR⁶¹R⁶²)_(e)—(CR⁶³R⁶⁴)_(f)—C(O)]—;

wherein a, b, c, d, e and f are independently 0 or 1, provided that atleast one of a and b is 1, at least one of c and d is 1, and at leastone of e and f is 1;

and wherein i, j and k are independently 0 or 1, provided that at leastone of i, j and k is 1;

D is a moiety derived from a GABA analog having the following structure:

wherein

R³ is a covalent bond linking the GABA analog moiety to J_(j);

R⁴ is hydrogen, or R⁴ and R⁹ together with the atoms to which they areattached form an azetidine, substituted azetidine, pyrrolidine orsubstituted pyrrolidine ring;

R⁵ and R⁶ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl;

R⁷ and R⁸ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, aryl, substitutedaryl, heteroaryl and substituted heteroaryl, or R⁷ and R⁸ together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclic or substituted heterocyclic ring;

R⁹ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryl andsubstituted heteroaryl;

R¹⁰ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryland substituted heteroaryl;

R¹¹ is C(O)R¹², wherein R² is a covalent bond linking the GABA analogmoiety to K_(k);

R⁵⁰ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl orR⁵⁰ and R⁵¹ together with the atoms to which they are attached form aheterocyclyl ring;

R⁵¹ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁵¹ and R⁵² together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁵¹ andR⁵³ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

R⁵² is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl;

R⁵³ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁵³ and R⁵⁴ together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

R⁵⁴ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl;

R⁵⁵ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl orR⁵⁵ and R⁵⁶, together with the atoms to which they are attached form aheterocyclyl ring;

R⁵⁶ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁵⁶ and R⁵⁷ together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁵⁶ andR⁵⁸ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

R⁵⁷ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl;

R⁵⁸ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁵⁸ and R⁵⁹ together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

R⁵⁹ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl;

R⁶⁰ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl orR⁶⁰ and R⁶¹, together with the atoms to which they are attached form aheterocyclyl ring;

R⁶¹ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁶¹ and R⁶² together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁶¹ andR⁶³ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

R⁶² is hydrogen, alkyl, substituted alkyl alkenyl substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl;

R⁶³ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁶³ and R⁶⁴ together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

R⁶⁴ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl;

and pharmaceutically acceptable salts, hydrates, and solvates thereof,

provided that if k is 0 then neither I nor J is derived from alanine,arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid,glycine, histidine, isoleucine, leucine, lysine, methionine,phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valineor phenylglycine;

and provided that when R⁵, R⁶, R⁹ and R¹⁰ are each hydrogen, then R⁷ andR⁸ are neither both hydrogen nor both methyl;

and yet further provided that when D is either of the following moieties

neither I nor J are selected from the group of moieties consisting ofH₂NCH₂C(O)—, H₂NCH(CH₃)C(O)—, NH₂CH₂CH₂C(O)— and

Preferably, in a compound of Formula (I), k is 0 and j is 1.

Preferably, D in a compound of Formula (I) is a moiety selected from agroup consisting of the following GABA analog moieties:

More preferably, D in a compound of Formula (I) is a moiety selectedfrom the group consisting of the following GABA analog moieties:

Preferably, in a compound of Formula (I), a and c are 1, and b and d are0.

Preferably, in a compound of Formula (I), i and k are 0, and j is 1.

Preferably, in a compound of Formula (I), k is 0, and i and j are 1.

Preferably, in a compound of Formula (I), i and j are 0, and k is 1.

Preferably, in a compound of Formula (I), i is 0, and j and k are 1.

Preferably, in a compound of Formula (I), I, J and K are not derivedfrom natural amino acids.

Preferably, in a compound of Formula (I), at least one of I, J and K arederived from the group comprising O-phosphoserine and O-phosphotyrosine.

More preferably, in a compound of Formula (I), i and k are 0, j is 1, cis 1 and d is 0.

Preferably, in a compound of Formula (I), when i and k are 0, j is 1, cis 1, and d is 0, then R⁵⁵ is hydrogen, R⁵⁷ is hydrogen and R⁵⁶ isselected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl and substitutedheteroaryl. More preferably, R⁵⁶ is selected from the group consistingof hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, substitutedaryl and heteroaryl.

Preferably, in a compound of Formula (I), when i and k are 0, j is 1, cis 1, d is 0, and R⁵⁷ is hydrogen, then R⁵⁵ and R⁵⁶ together with theatoms to which they are attached form a heterocyclyl or substitutedheterocyclyl ring. More preferably, R⁵⁵ and R⁵⁶ together with the atomsto which they are attached form an azetidine, 4-substituted pyrrolidine,piperidine or substituted piperidine ring.

Preferably, in a compound of Formula (I), when i and k are 0, j is 1, cis 1, d is 0, and R⁵⁵ is hydrogen, then R⁵⁶ and R⁵⁷ together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring. Morepreferably, R⁵⁶ and R⁵⁷ together with the atoms to which they areattached form a cyclopropyl, cyclobutyl, cyclopentyl, substitutedcyclopentyl, cyclohexyl, substituted cyclohexyl, piperidinyl orsubstituted piperidinyl ring.

In one embodiment of a compound of Formula (I), when i and k are 0, j is1, c is 1, d is 0, R⁵⁵ is hydrogen, R⁵⁷ is hydrogen and R⁵⁶ issubstituted alkyl, then preferably R⁵⁶ is selected from the groupconsisting of arylalkyl, substituted arylalkyl, heteroarylalkyl andsubstituted heteroarylalkyl. More preferably, R⁵⁶ is selected from thegroup consisting of substituted benzyl, s-naphthylmethyl, substituteds-naphthylmethyl, t-pyridylmethyl, substituted t-pyridylmethyl,t-quinolylmethyl, substituted t-quinolylmethyl, u-furanylmethyl,substituted u-furanylmethyl, u-benzofuranylmethyl, substituted u-benzofuranylmethyl, u-thienylmethyl, substituted u-thienylmethyl,u-benzothienylmethyl, substituted u-benzothienylmethyl,u-pyrrolylmethyl, substituted u-pyrrolylmethyl, substitutedu-indolylmethyl, u-pyrazinylmethyl, substituted u-pyrazinylmethyl,substituted v-imidazolylmethyl, v-oxazolylmethyl, substitutedv-oxazolylmethyl, v-thiazolylmethyl and substituted v-thiazolylmethyl,wherein s is 1 or 2; t is 2, 3 or 4; u is 2 or 3; and v is 2, 4 or 5.Even more preferably R⁵⁶ is selected from the group consisting of2-methylphenylmethyl, 3 methylphenylmethyl, 4-methylphenylmethyl,2-methoxyphenylmethyl, 3-methoxyphenylmethyl, 4-methoxyphenylmethyl,2-trifluoromethylphenylmethyl, 3-trifluoromethylphenylmethyl,4-trifluoromethylphenylmethyl, 2-cyanophenylmethyl, 3-cyanophenylmethyl,4-cyanophenylmethyl, 2-fluorophenylmethyl, 3-fluorophenylmethyl, 4fluorophenylmethyl, 2-chlorophenylmethyl, 3-chlorophenylmethyl,4-chlorophenylmethyl, 2-bromophenylmethyl, 3-bromophenylmethyl,4-bromophenylmethyl, 2-iodophenylmethyl, 3-iodophenylmethyl,4-iodophenylmethyl, 2,3-difluorophenylmethyl, 2,4-difluorophenylmethyl,2,5-difluorophenylmethyl, 2,6-difluorophenylmethyl,3,4-difluorophenylmethyl, 3,5-difluorophenylmethyl,2,3-dichlorophenylmethyl, 2,4-dichlorophenylmethyl,2,5-dichlorophenylmethyl, 2,6-dichlorophenylmethyl, 3,4dichlorophenylmethyl, 3,5-dichlorophenylmethyl, 1-naphthylmethyl,2-naphthylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl,2-quinolylmethyl, 3-quinolylmethyl, 4-quinolylmethyl, 2-furanylmethyl,3-furanylmethyl, 3-benzofuranylmethyl, 2-thienylmethyl, 3-thienylmethyl,3-benzothienylmethyl, 5-hydroxyindol-3-ylmethyl,5-alkoxyindol-3-ylmethyl, 5-acyloxyindol-3-ylmethyl, 2-oxazolylmethyl,4-oxazolylmethyl 2-thiazolylmethyl and 4-thiazolylmethyl.

In another embodiment of a compound of Formula (I), when i and k are 0,j is 1, c is 1, d is 0, R⁵⁵ is hydrogen, R⁵⁷ is hydrogen and R⁵⁶ issubstituted alkyl, then preferably R⁵⁶ is selected from the groupconsisting of —(CH₂)_(n)C(O)XR¹³ and —CH_(2[)4-C₆H₄—OC(O)R¹⁵], wherein:

n is 1 or 2;

X is C or NR¹⁴;

R¹³ and R¹⁴ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl and substituted heteroaryl, or R¹³ and R¹⁴ together with theatoms to which they are attached form a heterocyclyl or substitutedheterocyclyl ring; and

R¹⁵ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, alkoxy, substituted alkoxy, alkenyloxy, substitutedalkenyloxy, alkynyloxy, substituted alkynyloxy, cycloalkoxy, substitutedcycloalkoxy, heterocyclyloxy, substituted heterocyclyloxy, aryloxy,substituted aryloxy, heteroaryloxy and substituted heteroaryloxy;

with the provisos that when X is O, then R¹³ is not hydrogen; and when Xis NR¹⁴, then R¹³ and R¹⁴ are not both hydrogen.

Preferred compounds of Formula (I) are compounds selected from the groupconsisting of L-1-Naphthylalanine-Gabapentin,L-2-Naphthylalanine-Gabapentin, 1,2-Quinoylalaine-Gabapentin,L-(2-Quinoylalanine N-Oxide)-Gabapentin, L-2-Pyridylalanine-Gabapentin,L-3-Pyridylalanine-Gabapentin, L-(4-Pyridylalanine N-Oxide)-Gabapentin,L-2-Thienylalanine-Gabapentin, L-3-Thienylalanine-Gabapentin,1,3-Benzothienylalanine-Gabapentin, L-4-Thiazolylalanine-Gabapentin,L-2-Methylphenylalanine-Gabapentin, L-4-Methylphenylalanine-Gabapentin,L-2-Trifluoromethylphenylalanine-Gabapentin,L-3-Trifluoromethylphenylalanine-Gabapentin,L-4-Trifluoromethylphenylalanine-Gabapentin,L-2-Fluorophenylalanine-Gabapentin, L-3-Fluorophenylalanine-Gabapentin,L-4-Fluorophenylalanine-Gabapentin, L-2-Chlorophenylalanine-Gabapentin,L-3-Chlorophenylalanine-Gabapentin, L-4-Chlorophenylalanine-Gabapentin,L-4-Bromophenylalanine-Gabapentin, L-4 Iodophenylalanine-Gabapentin,L-2-Methoxyphenylalanine-Gabapentin,L-4-Methoxyphenylalanine-Gabapentin, L-4-Ethoxyphenylalanine-Gabapentin,L-3-Cyanophenylalanine-Gabapentin, L-4-Cyanophenylalanine-Gabapentin,L-3,4-Difluorophenylalanine-Gabapentin,L-3,5-Difluorophenylalanine-Gabapentin, D,L-2,4-Difluorophenylalanine-Gabapentin, D,L-2,6-Difluorophenylalanine-Gabapentin,L-2,4-Dichlorophenylalanine-Gabapentin,L-3,4-Dichlorophenylalanine-Gabapentin, L-Pipecolyl-Gabapentin,L-tert-Butylglycine-Gabapentin, L-2,3-Diaminopropionyl-Gabapentin,L-Norvaline-Gabapentin, L-Penicilamine-Gabapentin,1-Aminocyclopropane-1-Carbonyl-Gabapentin,1-Aminocyclohexane-1-Carbonyl-Gabapentin,L-Homophenylalanine-Gabapentin, L-Aspartyl-β-(Pyrrolidinyl)-Gabapentin,L-Aspartyl-β-(Butylamido)-Gabapentin,L-Aspartyl-β-(2-Methoxyethylamido)-Gabapentin,L-Aspartyl-β-(Piperidinyl)-Gabapentin,L-Aspartyl-β-(3-Methylbutylamido)-Gabapentin,L-Aspartyl-β-(Cyclohexylamido)-Gabapentin,L-Aspartyl-β-(4-Amidomethylpyridine)-Gabapentin,L-Aspartyl-β-(3-Amidomethylpyridine)-Gabapentin,L-Aspartyl-β-(Heptylamido)-Gabapentin,L-Aspartyl-β-(3,4-Dimethoxyphenethylamido)-Gabapentin,L-Aspartyl-β-(O-Cyclohexyl ester)-Gabapentin, L-Aspartyl-β-(O-Benzylester)-Gabapentin, L-Tyrosine-(O-2,6-Dimethylbenzoyl)-Gabapentin,L-Tyrosine-(O-2,6-Dimethoxybenzoyl)-Gabapentin,L-Tyrosine-(O-2-Methylbenzoyl)-Gabapentin,L-Tyrosine-(O-2-Bromobenzyloxycarbonyl)-Gabapentin,L-1-Naphthylalanine-Pregabalin, L-2-Naphthylalanine-Pregabalin,L-2-Quinoylalanine-Pregabalin, L-(2-Quinoylalanine N-Oxide)-Pregabalin,L-2-Pyridylalanine-Pregabalin, L-3-Pyridylalanine-Pregabalin,L-(4-Pyridylalanine N-Oxide)-Pregabalin, L-2-Thienylalanine-Pregabalin,L-3-Thienylalanine-Pregabalin, L-3-Benzothienylalanine-Pregabalin,L-4-Thiazolylalanine-Pregabalin, L-2-Methylphenylalanine-Pregabalin,L-4-Methylphenylalanine-Pregabalin,L-2-Trifluoromethylphenylalanine-Pregabalin,L-3-Trifluoromethylphenylalanine-Pregabalin,L-4-Trifluoromethylphenylalanine-Pregabalin,L-2-Fluorophenylalanine-Pregabalin, L-3-Fluorophenylalanine-Pregabalin,L-4-Fluorophenylalanine-Pregabalin, L-2-Chlorophenylalanine-Pregabalin,L-3-Chlorophenylalanine-Pregabalin, L-4-Chlorophenylalanine-Pregabalin,L-4-Bromophenylalanine-Pregabalin, L-4-Iodophenylalanine-Pregabalin,L-2-Methoxyphenylalanine-Pregabalin,L-4-Methoxyphenylalanine-Pregabalin, L-4-Ethoxyphenylalanine-Pregabalin,L-3-Cyanophenylalanine-Pregabalin, L-4-Cyanophenylalanine-Pregabalin,L-3,4-Difluorophenylalanine-Pregabalin,L-3,5-Difluorophenylalanine-Pregabalin, D,L-2,4-Difluorophenylalanine-Pregabalin, D,L-2,6-Difluorophenylalanine-Pregabalin,L-2,4-Dichlorophenylalanine-Pregabalin,L-3,4-Dichlorophenylalanine-Pregabalin, L-Pipecolyl-Pregabalin,L-tert-Butylglycine-Pregabalin, L-2,3-Diaminopropionyl-Pregabalin,L-Norvaline-Pregabalin, L-Penicillamine-Pregabalin,1-Aminocyclopropane-1-Carbonyl-Pregabalin,1-Aminocyclohexane-1-Carbonyl-Pregabalin,L-Homophenylalanine-Pregabalin, L-Aspartyl-β-(Pyrrolidinyl)-Pregabalin,L-Aspartyl-β-(Butylamido)-Pregabalin,L-Aspartyl-β-(2-Methoxyethylamido)-Pregabalin,L-Aspartyl-β-(Piperidinyl)-Pregabalin,L-Aspartyl-β-(3-Methylbutylamido)-Pregabalin,L-Aspartyl-β-(Cyclohexylamido)-Pregabalin,L-Aspartyl-β-(4-Amidomethylpyridine)-Pregabalin,L-Aspartyl-β-(3-Amidomethylpyridine)-Pregabalin,L-Aspartyl-β-(Heptylamido)-Pregabalin,L-Aspartyl-β-(3,4-Dimethoxyphenethylamido)-Pregabalin,L-Aspartyl-β-(O-Cyclohexyl ester)-Pregabalin, L-Aspartyl-β-(O-Benzylester)-Pregabalin, L-Tyrosine-(O-2,6-Dimethylbenzoyl)-Pregabalin,L-Tyrosine-(O-2,6-Dimethoxybenzoyl)-Pregabalin,L-Tyrosine-(O-2-Methylbenzoyl)-Pregabalin andL-Tyrosine-(O-2-Bromobenzyloxycarbonyl)-Pregabalin.

These compounds serve as substrates for the peptide transporters PEPT1and PEPT2 from both human and rat. Further, in vitro metabolism studiesdemonstrate that these compounds function as prodrugs of gabapentin orpregabalin respectively, undergoing partial or complete conversion tothe parent drug after incubation with tissue extracts or isolatedenzymes found in gastric fluid or plasma, as described in detail in theExperimental section.

In a preferred embodiment, the compound of Formula (I) is sufficientlystable such that less than 50% of the compound is metabolized afterincubation in vitro with Caco-2 homogenate for 1 hour, as described inmore detail in Example 6.

Preferred compounds of Formula (I) are prodrugs of GABA analogs that areabsorbed from the gastrointestinal tract in mammals by interaction withintestinal peptide transporters. It is particularly preferred that theseGABA analog prodrugs be sufficiently stable within the intestinal lumento be absorbed intact into the systemic circulation, but then undergoefficient conversion back to the GABA analog. This provides a method forachieving better dose-proportional drug exposure than can be attained byoral administration of the parent GABA analog itself, since the PEPTtransport pathway is less susceptible to saturation (at high substratedoses) than the large neutral amino acid transport system typicallyutilized by GABA analogs.

In one preferred embodiment, a compound of Formula (I), upon oraladministration to a patient in need of therapy, provides therapeuticallyefficacious levels of the GABA analog in the plasma of the patient,where the concentration of the GABA analog in plasma of the patient overtime provides a curve of concentration of the GABA analog in the plasmaover time, the curve having an area under the curve (AUC) which issubstantially more proportional to the dose of GABA analog administered,as compared to the proportionality achieved following oraladministration of the GABA analog itself. In another preferredembodiment, a compound of Formula (I), upon oral administration to apatient in need of therapy, provides therapeutically efficacious levelsof the GABA analog in the plasma of a patient, where the concentrationof the GABA analog in plasma of the patient over time provides a curveof concentration of the GABA analog in the plasma over time, the curvehaving a maximum plasma concentration (C_(max)) which is substantiallymore proportional to the dose of GABA analog administered, as comparedto the proportionality achieved following oral administration of theGABA analog itself.

Prodrugs of GABA analogs that are substrates for the peptide transporterPEPT1 are candidates for formulation in sustained release oral dosageforms. Preferred compounds of Formula (I) are prodrugs of GABA analogsthat are absorbed from the mammalian colon. Following colonicadministration of these prodrugs, the maximum plasma concentrations ofthe GABA analog, as well as the area under the GABA analog plasmaconcentration vs. time curves, are significantly greater (>3-fold) thanthat produced from colonic administration of the GABA analog itself.

Particularly preferred compounds of Formula (I) are compounds selectedfrom the group consisting of L-2-Thienylalanine-Gabapentin,L-4-Methylphenylalanine-Gabapentin,L-4-Trifluoromethylphenylalanine-Gabapentin,L-2-Fluorophenylalanine-Gabapentin, L-4-Fluorophenylalanine-Gabapentin,L-2-Chlorophenylalanine-Gabapentin, L-4-Chlorophenylalanine-Gabapentin,L-4-Bromophenylalanine-Gabapentin, L-4-Iodophenylalanine-Gabapentin,L-4-Methoxyphenylalanine-Gabapentin, L-4-Ethoxyphenylalanine-Gabapentin,L-4-Cyanophenylalanine-Gabapentin,L-3,4-Difluorophenylalanine-Gabapentin, D,L-2,4-Difluorophenylalanine-Gabapentin, D,L-2,6-Difluorophenylalanine-Gabapentin,L-2,4-Dichlorophenylalanine-Gabapentin andL-3,4-Dichlorophenylalanine-Gabapentin.

In one aspect, this invention is directed to a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof Formula (I) and a pharmaceutically acceptable carrier. Thepharmaceutical composition may be used to treat or prevent epilepsy,depression, anxiety, psychosis, faintness attacks, hypokinesia, cranialdisorders, neurodegenerative disorders, panic, pain (especiallyneuropathic pain, muscular pain or skeletal pain), inflammatory disease,insomnia, gastrointestinal disorders or ethanol withdrawal syndrome in apatient.

In another aspect, this invention is directed to sustained release oraldosage forms comprising a therapeutically effective amount of a compoundof Formula (I) and, optionally, a pharmaceutically acceptable carrier.In one embodiment, the dosage form comprises an osmotic dosage form. Inanother embodiment, the dosage form comprises a prodrug-releasingpolymer. In another embodiment, the dosage form comprises aprodrug-releasing lipid. In another embodiment, the dosage formcomprises a prodrug-releasing wax. In another embodiment, the dosageform comprises tiny timed-release pills. In yet another embodiment, thedosage form comprises prodrug releasing beads. Preferably, the prodrugis released from the dosage form over a period of at least about 6hours, more preferably at least about 8 hours, and most preferably atleast about 12 hours. Further, the dosage form preferably releases from0 to 20% of the prodrug in 0 to 2 hours, from 20 to 50% of the prodrugin 2 to 12 hours, from 50 to 85% of the prodrug in 3 to 20 hours andgreater than 75% of the prodrug in 5 to 18 hours.

In another aspect, this invention is directed to a method for treatingor preventing epilepsy, depression, anxiety, psychosis, faintnessattacks, hypokinesia, cranial disorders, neurodegenerative disorders,panic, pain (especially neuropathic pain, muscular pain or skeletalpain), inflammatory disease, insomnia, gastrointestinal disorders orethanol withdrawal syndrome in a patient. The method comprisesadministering to a patient in need of such therapy a therapeuticallyeffective amount of a compound of Formula (I), optionally with apharmaceutically acceptable vehicle.

In another aspect, this invention is directed to a method for achievingsustained release of a GABA analog in a patient in need of therapy. Themethod comprises orally administering to the patient a sustained releasedosage form containing a therapeutically effective amount of a compoundof Formula (I), and optionally, a pharmaceutically acceptable vehicle.

In yet another aspect, this invention is directed to a method forachieving improved dose-proportional exposure of a GABA analog in apatient, said method comprising orally administering to the patient atherapeutically effective amount of a compound of Formula (I) and,optionally, a pharmaceutically acceptable vehicle.

Compound Preparation

Compounds of this invention can be made by various methods, includingthose illustrated in FIGS. 1-3 and the working examples provided below.

The starting materials and reagents used in preparing these compoundsare either available from commercial suppliers such as Aldrich ChemicalCo., (Milwaukee, Wis., USA), Bachem (Torrance, Calif., USA),Erika-Chemie, or Sigma (St. Louis, Mo., USA) or are prepared by methodsknown to those skilled in the art following procedures set forth inreferences such as Fieser and Fieser's Reagents for Organic Synthesis,Volumes 1-15 (John Wiley and Sons, 1.991); Rodd's Chemistry of CarbonCompounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers,1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991),March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition),and Larock's Comprehensive Organic Transformations (VCH Publishers Inc.,1989). These schemes are merely illustrative of some methods by whichthe compounds of this invention can be synthesized, and variousmodifications to these schemes can be made and will be suggested to oneskilled in the art having referred to this disclosure.

The starting materials and the intermediates of the reaction may beisolated and purified if desired using conventional techniques,including but not limited to filtration, distillation, crystallization,chromatography, and the like. Such materials may be characterized usingconventional means, including physical constants and spectral data.

Pharmaceutical Formulations

When employed as pharmaceuticals, the compounds of Formula (I) areusually administered in the form of pharmaceutical compositions. Thesecompounds can be administered by a variety of routes including oral,rectal, subcutaneous, intravenous, intramuscular and intranasal. Oraladministration of these compounds and compositions is particularlypreferred. Such compositions are prepared in a manner well known in thepharmaceutical art and comprise at least one active compound.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, one or more of the compounds of Formula (I)above associated with pharmaceutically acceptable carriers. In makingthe compositions of this invention, the active ingredient is usuallymixed with an excipient, diluted by an excipient or enclosed within sucha carrier, which can be in the form of a capsule, sachet, paper or othercontainer. When the excipient serves as a diluent, it can be a solid,semi-solid, or liquid material, which acts as a vehicle, carrier ormedium for the active ingredient. Thus, the compositions can be in theform of tablets, pills, powders, lozenges, sachets, cachets, elixirs,suspensions, emulsions, solutions, syrups, aerosols (as a solid or in aliquid medium), ointments containing, for example, up to 10% by weightof the active compound, soft and hard gelatin capsules, suppositories,sterile injectable solutions, and sterile packaged powders.

In preparing a formulation, it may be necessary to mill the activecompound to provide the appropriate particle size prior to combiningwith other ingredients. If the active compound is substantiallyinsoluble, it ordinarily is milled to a particle size of less than 200mesh. If the active compound is substantially water soluble, theparticle size is normally adjusted by milling to provide a substantiallyuniform distribution in the formulation, e.g. about 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulations can additionally include: lubricating agentssuch as talc, magnesium stearate, and mineral oil; wetting agents;emulsifying and suspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions are preferably formulated in a unit dosage form, eachdosage containing from about 0.1 to about 5000 mg, more usually about 10to about 2000 mg, of the active ingredient. The term “unit dosage forms”refers to physically discrete units suitable as unitary dosages forhuman subjects and other animals, each unit containing a predeterminedquantity of active material calculated to produce the desiredtherapeutic effect, in association with a suitable pharmaceuticalexcipient.

The active compound is effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It, willbe understood, however, that the amount of the compound actuallyadministered will be determined by a physician, in the light of therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredient is dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, 0.1 mg to about 2 g of the activeingredient of the present invention.

The tablets or pills of the present invention may be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solventsor mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. Preferably the compositions are administered by the oral or nasalrespiratory route for local or systemic effect. Compositions inpreferably pharmaceutically acceptable solvents may be nebulized by useof inert gases. Nebulized solutions may be breathed directly from thenebulizing device or the nebulizing device may be attached to a facemasks tent, or intermittent positive pressure breathing machine.Solution, suspension, or powder compositions may be administered,preferably orally or nasally, from devices which deliver the formulationin an appropriate manner.

The present compounds and/or compositions of the invention, whichcomprise one or more compounds of the invention, are preferablyadministered orally. In particularly preferred embodiments, thecompounds of the invention may be delivered via sustained releasesystems, preferably oral sustained release systems. Sustained releasedosage forms for oral administration are described in greater detailbelow.

Sustained Release Oral Dosage Forms of the Invention

The present invention can be practiced with a number of different dosageforms, which may be adapted to provide sustained release of the prodrugupon oral administration.

In one embodiment of the invention, the dosage form comprises beads thaton dissolution or diffusion release the prodrug over an extended periodof hours, preferably, over a period of at least 6 hours, morepreferably, over a period of at least 8 hours and most preferably, overa period of at least 12 hours. The prodrug-releasing beads may have acentral composition or core comprising a prodrug and pharmaceuticallyacceptable vehicles, including an optional lubricant, antioxidant andbuffer. The beads may be medical preparations with a diameter of about 1to 2 mm. Individual beads may comprise doses of the prodrug, forexample, doses of up to about 40 mg of prodrug. The beads, in oneembodiment, are formed of non-cross-linked materials to enhance theirdischarge from the gastrointestinal tract. The beads may be coated witha release rate-controlling polymer that gives a timed release profile.

The time release beads may be manufactured into a tablet fortherapeutically effective prodrug administration. The beads can be madeinto matrix tablets by the direct compression of a plurality of beadscoated with, for example, an acrylic resin and blended with excipientssuch as hydroxypropylmethyl cellulose. The manufacture of beads has beendisclosed in the art (Lu, Int. J. Pharm., 1994, 112, 117-124;Pharmaceutical Sciences by Remington, 14th ed, pp 1626-1628 (1970);Fincher, J. Pharm. Sci. 1968, 57, 1825-1835 ( ); and U.S. Pat. No.4,083,949) as has the manufacture of tablets (Pharmaceutical Sciences,by Remington, 17th Ed, Ch. 90, pp 1603-1625 (1985).

In another embodiment, an oral sustained release pump may be used (seeLanger, supra; Sefton, 1987, CRC Crit Ref Biomed Eng. 14:201; Saudek etal., 1989, N. Engl. J Med. 321:574).

In another embodiment, polymeric materials can be used (see “MedicalApplications of Controlled Release,” Langer and Wise (eds.), CRC Press,Boca Raton, Fla. (1974); “Controlled Drug Bioavailability,” Drug ProductDesign and Performance, Smolen and Ball (eds.), Wiley, New York (1984);Ranger and Peppas, 1983, J Macromol. Sci. Rev. Macromol Chem. 23:61; seealso Levy et al., 1985, Science 228: 190; During et al., 1989, Ann.Neurol. 25:351; Howard et al, 1989, J. Neurosurg. 71:105). In apreferred embodiment, polymeric materials are used for oral sustainedrelease delivery. Preferred polymers include sodiumcarboxymethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose and hydroxyethylcellulose (most preferred,hydroxypropylmethylcellulose). Other preferred cellulose ethers havebeen described (Alderman, Int. J. Pharm. Tech. & Prod. Mfr., 1984, 5(3)1-9). Factors affecting drug release are well known to the skilledartisan and have been described in the art (Bamba et al., Int. J.Pharm., 1979, 2, 307).

In another embodiment, enteric-coated preparations can be used for oralsustained release administration. Preferred coating materials includepolymers with a pH-dependent solubility (i.e., pH-controlled release),polymers with a slow or pH-dependent rate of swelling, dissolution orerosion (i.e., time-controlled release), polymers that are degraded byenzymes (i.e., enzyme-controlled release) and polymers that form firmlayers that are destroyed by an increase in pressure (i.e.,pressure-controlled release).

In yet another embodiment, drug-releasing lipid matrices can be used fororal sustained release administration. One particularly preferredexample is when solid microparticles of the prodrug are coated with athin controlled release layer of a lipid (e.g., glyceryl behenate and/orglyceryl palmitostearate) as disclosed in Farah et al., U.S. Pat. No.6,375,987 and Joachim et al., U.S. Pat. No. 6,379,700. The lipid-coatedparticles can optionally be compressed to form a tablet. Anothercontrolled release lipid-based matrix material which is suitable forsustained release oral administration comprises polyglycolizedglycerides as disclosed in Roussin et al., U.S. Pat. No. 6,171,615.

In yet another embodiment, prodrug-releasing waxes can be used for oralsustained release administration. Examples of suitable sustainedprodrug-releasing waxes are disclosed in Cain et al., U.S. Pat. No.3,402,240 (carnauba wax, candedilla wax, esparto wax and ouricury wax);Shtohryn et al. U.S. Pat. No. 4,820,523 (hydrogenated vegetable oil,bees wax, caranuba wax, paraffin, candelillia, ozokerite and mixturesthereof); and Walters, U.S. Pat. No. 4,421,736 (mixture of paraffin andcastor wax).

In still another embodiment, osmotic delivery systems are used for oralsustained release administration (Verma et al., Drug Dev. Ind. Pharm.,2000, 26:695-708). In a preferred embodiment, OROSâ systems made by AlzaCorporation, Mountain View, Calif. are used for oral sustained releasedelivery devices (Theeuwes et al., U.S. Pat. No. 3,845,770; Theeuwes etal., U.S. Pat. No. 3,916,899).

In yet another embodiment, a controlled-release system can be placed inproximity of the target of the prodrug of the GABA analog, thusrequiring only a fraction of the systemic dose (see, e.g., Goodson, in“Medical Applications of Controlled Release,” supra, vol. 2, pp. 115-138(1984)). Other controlled-release systems discussed in Langer, 1990,Science 249:1527-1533 may also be used.

In another embodiment of the invention, the dosage form comprises aprodrug of a GABA analog coated on a polymer substrate. The polymer canbe an erodible, or a nonerodible polymer. The coated substrate may befolded onto itself to provide a bilayer polymer drug dosage form. Forexample prodrug of a GABA analog can be coated onto a polymer such as apolypeptide, collagen, gelatin, polyvinyl alcohol, polyorthoester,polyacetyl, or a polyorthocarbonate and the coated polymer folded ontoitself to provide a bilaminated dosage form. In operation, thebioerodible dosage form erodes at a controlled rate to dispense theprodrug over a sustained release period. Representative biodegradablepolymer comprise a member selected from the group consisting ofbiodegradable poly(amides), poly(amino acids), poly(esters), poly(lacticacid), poly(glycolic acid), poly(carbohydrate), poly(orthoester),poly(orthocarbonate), poly(acetyl), poly(anhydrides), biodegradablepoly(dehydropyrans), and poly(dioxinones) which are known in the art(Rosoff, Controlled Release of Drugs, Chap. 2, pp. 53-95 (1989); and inU.S. Pat. Nos. 3,811,444; 3,962,414; 4,066,747, 4,070,347; 4,079,038;and 4,093,709).

In another embodiment of the invention, the dosage form comprises aprodrug loaded into a polymer that releases the prodrug by diffusionthrough a polymer, or by flux through pores or by rupture of a polymermatrix. The drug delivery polymeric dosage form comprises aconcentration of 10 mg to 2500 mg homogenously contained in or on apolymer. The dosage form comprises at least one exposed surface at thebeginning of dose delivery. The non-exposed surface, when present, iscoated with a pharmaceutically acceptable material impermeable to thepassage of a prodrug. The dosage form may be manufactured by proceduresknown in the art. An example of providing a dosage form comprisesblending a pharmaceutically acceptable carrier like polyethylene glycol,with a known dose of prodrug at an elevated temperature, like 37° C.,and adding it to a silastic medical grade elastomer with a cross-linkingagent, for example, octanoate, followed by casting in a mold. The stepis repeated for each optional successive layer. The system is allowed toset for 1 hour, to provide the dosage form. Representative polymers formanufacturing the dosage form comprise a member selected from the groupconsisting of olefin, and vinyl polymers, addition polymers,condensation polymers, carbohydrate polymers, and silicon polymers asrepresented by polyethylene, polypropylene, polyvinyl acetate,polymethylacrylate, polyisobutylmethacrylate, poly alginate, polyamideand polysilicon. The polymers and procedures for manufacturing them havebeen described in the art (Coleman et al., Polymers 1990, 31, 1187-1231;Roerdink et al., Drug Carrier Systems 1989, 9, 57-10; Leong et al., Adv.Drug Delivery Rev. 1987, 1, 199-233; Roff et al., Handbook of CommonPolymers 1971, CRC Press; U.S. Pat. No. 3,992,518).

In another embodiment of the invention, the dosage from comprises aplurality of tiny pills. The tiny time-released pills provide a numberof individual doses for providing various time doses for achieving asustained-release prodrug delivery profile over an extended period oftime up to 24 hours. The matrix comprises a hydrophilic polymer selectedfrom the group consisting of a polysaccharide, agar, agarose, naturalgum, alkali alginate including sodium alginate, carrageenan, fucoidan,furcellaran, laminaran, hypnea, gum arabic, gum ghatti, gum karaya, grumtragacanth, locust bean gum, pectin, amylopectin, gelatin, and ahydrophilic colloid. The hydrophilic matric comprises a plurality of 4to 50 tiny pills, each tiny pill comprise a dose population of from 10ng, 0.5 mg, 1 mg, 1.2 mg, 1.4 mg, 1.6 mg, 5.0 mg etc. The tiny pillscomprise a release rate-controlling wall of 0.001 up to 1.0 mm thicknessto provide for the timed release of prodrug. Representative wall formingmaterials include a triglyceryl ester selected from the group consistingof glyceryl tristearate, glyceryl monostearate, glyceryl dipalmitate,glyceryl laureate, glyceryl didecenoate and glyceryl tridenoate. Otherwall forming materials comprise polyvinyl acetate, phthalate,methylcellulose phthalate and microporous olefins. Procedures formanufacturing tiny pills are disclosed in U.S. Pat. Nos. 4,434,153;4,721,613; 4,853,229; 2,996,431; 3,139,383 and 4,752,470.

In another embodiment of the invention, the dosage form comprises anosmotic dosage form, which comprises a semipermeable wall that surroundsa therapeutic composition comprising the prodrug. In use within apatient, the osmotic dosage form comprising a homogenous compositionimbibes fluid through the semipermeable wall into the dosage form inresponse to the concentration gradient across the semipermeable wall.The therapeutic composition in the dosage form develops osmotic energythat causes the therapeutic composition to be administered through anexit from the dosage form over a prolonged period of time up to 24 hours(or even in some cases up to 30 hours) to provide controlled andsustained prodrug release. These delivery platforms can provide anessentially zero order delivery profile as opposed to the spikedprofiles of immediate release formulations.

In another embodiment of the invention, the dosage form comprisesanother osmotic dosage form comprising a wall surrounding a compartment,the wall comprising a semipermeable polymeric composition permeable tothe passage of fluid and substantially impermeable to the passage ofprodrug present in the compartment, a prodrug-containing layercomposition in the compartment, a hydrogel push layer composition in thecompartment comprising an osmotic formulation for imbibing and absorbingfluid for expanding in size for pushing the prodrug composition layerfrom the dosage form, and at least one passageway in the wall forreleasing the prodrug composition. The method delivers the prodrug byimbibing fluid through the semipermeable wall at a fluid imbibing ratedetermined by the permeability of the semipermeable wall and the osmoticpressure across the semipermeable wall causing the push layer to expand,thereby delivering the prodrug from the dosage form through the exitpassageway to a patient over a prolonged period of time (up to 24 oreven 30 hours). The hydrogel layer composition may comprise 10 mg to1000 mg of a hydrogel such as a member selected from the groupconsisting of a polyalkylene oxide of 1,000,000 to 8,000,000 which areselected from the group consisting of a polyethylene oxide of 1,000,000weight-average molecular weight, a polyethylene oxide of 2,000,000molecular weight, a polyethylene oxide of 4,000,000 molecular weight, apolyethylene oxide of 5,000,000 molecular weight, a polyethylene oxideof 7,000,000 molecular weight and a polypropylene oxide of the 1,000,000to 8,000,000 weight-average molecular weight; or 10 mg to 1000 mg of analkali carboxymethylcellulose of 10,000 to 6,000,000 weight averagemolecular weight, such as sodium carboxymethylcellulose or potassiumcarboxymethylcellulose. The hydrogel expansion layer comprises 0.0 mg to350 mg, in present manufacture; 0.1 mg to 250 mg of ahydroxyalkylcellulose of 7,500 to 4,500,00 weight-average molecularweight (e.g., hydroxymethylcellulose, hydroxyethylcellulose,hydroxypropylcellulose, hydroxybutylcellulose or hydroxypentylcellulose)in present manufacture; 1 mg to 50 mg of an osmagent selected from thegroup consisting of sodium chloride, potassium chloride, potassium acidphosphate, tartaric acid, citric acid, raffinose, magnesium sulfate,magnesium chloride, urea, inositol, sucrose, glucose and sorbitol; 0 to5 mg of a colorant, such as ferric oxide; 0 mg to 30 mg, in a presentmanufacture, 0.1 mg to 30 mg of a hydroxypropylalkylcellulose of 9,000to 225,000 average-number molecular weight, selected from the groupconsisting of hydroxypropylethylcellulose, hydroxypropypentylcellulose,hydroxypropylmethylcellulose, and hydropropylbutylcellulose; 0.00 to 1.5mg of an antioxidant selected from the group consisting of ascorbicacid, butylated hydroxyanisole, butylatedhydroxyquinone,butylhydroxyanisol, hydroxycomarin, butylated hydroxytoluene, cephalm,ethyl gallate, propyl gallate, octyl gallate, lauryl gallate,propyl-hydroxybenzoate, trihydroxybutylrophenone, dimethylphenol,dibutylphenol, vitamin E, lecithin and ethanolamine; and 0.0 mg to 7 mgof a lubricant selected from the group consisting of calcium stearate,magnesium stearate, zinc stearate, magnesium oleate, calcium palmitate,sodium suberate, potassium laureate, salts of fatty acids, salts ofalicyclic acids, salts of aromatic acids, stearic acid, oleic acid,palmitic acid, a mixture of a salt of a fatty, alicyclic or aromaticacid, and a fatty, alicyclic, or aromatic acid.

In the osmotic dosage forms, the semipermeable wall comprises acomposition that is permeable to the passage of fluid and impermeable tothe passage of prodrug. The wall is nontoxic and comprises a polymerselected from the group consisting of a cellulose acylate, cellulosediacylate, cellulose triacylate, cellulose acetate, cellulose diacetateand cellulose triacetate. The wall comprises 75 wt % (weight percent) to100 wt % of the cellulosic wall-forming polymer; or, the wall cancomprise additionally 0.01 wt % to 80 wt % of polyethylene glycol, or 1wt % to 25 wt % of a cellulose ether selected from the group consistingof hydroxypropylcellulose or a hydroxypropylalkycellulose such ashydroxypropylmethylcellulose. The total weight percent of all componentscomprising the wall is equal to 100 wt %. The internal compartmentcomprises the prodrug-containing composition alone or in layeredposition with an expandable hydrogel composition. The expandablehydrogel composition in the compartment increases in dimension byimbibing the fluid through the semipermeable wall, causing the hydro gelto expand and occupy space in the compartment, whereby the drugcomposition is pushed from the dosage form. The therapeutic layer andthe expandable layer act together during the operation of the dosageform for the release of prodrug to a patient over time. The dosage formcomprises a passageway in the wall that connects the exterior of thedosage form with the internal compartment. The osmotic powered dosageform provided by the invention delivers prodrug from the dosage form tothe patient at a zero order rate of release over a period of up to about24 hours.

The expression “passageway” as used herein comprises means and methodssuitable for the metered release of the prodrug from the compartment ofthe dosage form. The exit means comprises at least one passageway,including orifice, bore, aperture, pore, porous element, hollow fiber,capillary tube, channel, porous overlay, or porous element that providesfor the osmotic controlled release of prodrug. The passageway includes amaterial that erodes or is leached from the wall in a fluid environmentof use to produce at least one controlled-release dimensionedpassageway. Representative materials suitable for forming a passageway,or a multiplicity of passageways comprise a leachable poly(glycolic)acid or poly(lactic) acid polymer in the wall, a gelatinous filament,poly(vinyl alcohol), leach-able polysaccharides, salts, and oxides. Apore passageway, or more than one pore passageway, can be formed byleaching a leachable compound, such as sorbitol, from the wall. Thepassageway possesses controlled-release dimensions, such as round,triangular, square and elliptical, for the metered release of prodrugfrom the dosage form. The dosage form can be constructed with one ormore passageways in spaced apart relationship on a single surface or onmore than one surface of the wall. The expression “fluid environment”denotes an aqueous or biological fluid as in a human patient, includingthe gastrointestinal tract. Passageways and equipment for formingpassageways are disclosed in U.S. Pat. Nos. 3,845,770; 3,916,899;4,063,064; 4,088,864 and 4,816,263. Passageways formed by leaching aredisclosed in U.S. Pat. Nos. 4,200,098 and 4,285,987.

Regardless of the specific form of sustained release oral dosage formused, the prodrug is preferably released from the dosage form over aperiod of at least about 6 hours, more preferably, over a period of atleast about 8 hours, and most preferably, over a period of at leastabout 1.2 hours. Further, the dosage form preferably releases from 0 to20% of the prodrug in 0 to 2 hours, from 20 to 50% of the prodrug in 2to 12 hours, from 50 to 85% of the prodrug in 3 to 20 hours and greaterthan 75% of the prodrug in 5 to 18 hours. The sustained release oraldosage form further provides a concentration of the GABA analog in theblood plasma of the patient over time, which curve has an area under thecurve (AUC) that is proportional to the dose of the prodrug of GABAanalog administered, and a maximum concentration Cmax. The Cmax is lessthan 75%, and is preferably, less than 60%, of the Cmax obtained fromadministering an equivalent dose of the prodrug from an immediaterelease oral dosage form, and the AUC is substantially the same as theAUC obtained from administering an equivalent dose of the prodrug froman immediate release oral dosage form.

Preferably, the dosage forms of the invention are administered twice perday (more preferably, once per day).

The following synthetic and biological examples are offered toillustrate this invention and are not to be construed in any way aslimiting the scope of this invention. Unless otherwise stated, alltemperatures are in degrees Celsius.

EXAMPLES

In the examples below, the following abbreviations have the followingmeanings. If an abbreviation is not defined, it has its generallyaccepted meaning.

-   -   Atm=atmosphere    -   Boc=ter-t-butyloxycarbonyl    -   Cbz=carbobenzyloxy    -   CPM=counts per minute    -   DCC=dicyclohexylcarbodiimide    -   DMAP=4-N,N-dimethylaminopyridine    -   DMF=N,N-dimethylformamide    -   DMSO=dimethylsulfoxide    -   Fmoc=9-fluorenylmethyloxycarbonyl    -   g=gram    -   h=hour    -   HBSS=Hank's buffered saline solution    -   HBTU=O-Benzotriazolyl tetra-N-methyl-uronium hexafluorophosphate    -   L=liter    -   LC/MS=liquid chromatography/mass spectroscopy    -   M=molar    -   min=minute    -   mL=milliliter    -   mmol=millimoles    -   NADPH=nicotinamide-adenine dinucleotide phosphate    -   NHS=N-hydroxysuccinimide    -   THF tetrahydrofuran    -   TFA=trifluoroacetic acid    -   TMS=trimethylsilyl    -   μL=microliter    -   μM=micromolar    -   v/v=volume to volume

Experimental Methods Example 1 Preparation of Aminoacyl-GabapentinDerivatives Method 1

To a 40 mL vial was added an N-Boc-protected amino acid (5 mmol),dicyclohexylcarbodiimide (1.24 g, 6 mmol), N-hydroxysuccinimide (0.7 g,6 mmol), and acetonitrile (20 mL). The reaction mixture was shaken at22-25° C. for 4 h. The precipitated dicyclohexylurea was removed byfiltration. To the filtrate was added an aqueous solution (30 mL) ofgabapentin hydrochloride (1.04 g, 6 mmol), and sodium hydroxide (0.4 g,10 mmol). The reaction was stirred at 22-25 C for 16 h. The reactionmixture was diluted with ethyl acetate (100 mL) and washed with 0.5 Maqueous citric acid (2×100 mL) and water (2×100 mL). The organic phasewas separated, dried (MgSO₄), filtered and concentrated under reducedpressure. The residue was dissolved in trifluoroacetic acid (40 ml) andallowed to stand at 22-25° C. for 2 h. The solvent was removed underreduced pressure. The residue was dissolved in water (4 mL) and filteredthrough a 0.25 μM nylon membrane filter prior to purification bypreparative HPLC (Phenomenex 250×21.2 mm, 5 μm LUNA C18 column, 100%water for 5 minutes, then 0-60% acetonitrile in water with 0.05% TFAover 20 minutes at 20 mL/min). The pure fractions were combined and thesolvent was removed under reduced pressure to afford the product (1)(typically 70-90%) as a white solid.

The following compounds were prepared according to the method describedabove:

β-Alanine-Gabapentin (1a): MS (ESI) m/z 241.23 (M−H⁺), 243.26 (M+H⁺)

α-Aminoisobutyryl-Gabapentin (1b): MS (ESI) m/z 255.26 (M−H⁻), 257.28(M+H⁺)

D-Alanine-Gabapentin (1c): MS (ESI) m/z 241.24 (M−H⁻), 243.27 (M+H⁺)

N-Methyl-Glycine-Gabapentin (1d): MS (ESI) m/z 241.24 (M−H⁻), 243.28(M+H⁺)

N-Methyl-L-Valine-Gabapentin (1e): MS (ESI) m/z 283.42 (M−H⁻), 285.34(M+H⁺).

N-Methyl-L-Serine-Gabapentin (1f): MS (ESI) m/z 271.38 (M−H⁻), 273.41(M+H⁺).

N-Methyl-L-Alanine-Gabapentin (1g): MS (ESI) m/z 255.29 (M−H⁻), 257.29(M+H⁻).

L-Pipecolyl-Gabapentin (1h): MS (ESI) m/z 281.23 (M−H⁻), 283.15 (M+H⁺).

L-tert-Butylglycine-Gabapentin (1i): MS (ESI) m/z 283.42 (M−H⁻), 285.2(M+H⁺).

L-2,3-Diaminopropionyl-Gabapentin (1j): MS (ESI) m/z 256.3 (M−H⁻), 258.3(M+M⁺).

L-Norvaline-Gabapentin (1k): MS (ESI) m/z 269.2 (M−H⁻), 271.24 (M+H⁺).

L-1-Naphthylalanine-Gabapentin (1l): MS (ESI) m/z 367.2 M−H⁻), 369.21(M+H⁺).

L-2-Naphthylalanine-Gabapentin (1m): MS (ESI) m/z 367.23 (M−H⁻), 369.3(M+H⁺).

L-2-Quinoylalanine-Gabapentin (1n): MS (ESI) m/z 368.18 (M−H⁻), 370.28(M+H⁺).

-   L-(2-Quinoylalanine N-Oxide)-Gabapentin (1o): MS (ESI) m/z 384.25    (M−H⁻), 386.87 (M+H⁺).

L-2-Pyridylalanine-Gabapentin (1p): MS (ESI) m/z 318.23 (M−H⁻),320.2+H⁺).

L-3-Pyridylalanine-Gabapentin (1q): MS (ESI) m/z 318.21 (M−H⁻), 320.15(M+H⁺).

L-(4-Pyridylalanine N-Oxide)-Gabapentin (1r): MS (ESI) m/z 334.24(M−H⁻), 336.24 (M+H⁺).

L-2-Thienylalanine-Gabapentin (1s): MS (ESI) m/z 323.24 (M−H⁻).

L-3-Thienylalanine-Gabapentin (1t): MS (ESI) m/z 323.24 (M−H⁻), 325.37(M+H⁺).

L-3-Benzothienylalanine-Gabapentin (1u): MS (ESI) m/z 373.26 (M−H⁻).

L-4-Thiazolylalanine-Gabapentin (1v): MS (ESI) m/z 324.25 (M−H⁻).

L-2-Methylphenylalanine-Gabapentin (1w): MS (ESI) m/z 331.28 (M−H⁻)333.6 (M+H⁺).

L-4-Methylphenylalanine-Gabapentin (1x): MS (ESI) m/z 331.3 (M−H⁻).

L-2-Trifluoromethylphenylalanine-Gabapentin (1y): MS (ESI) m/z 385.28(M−H⁻), 387.61 (M+H⁺).

L-3-Trifluoromethylphenylalanine-Gabapentin (1z): MS (ESI) m/z 385.23(M−H⁻), 387.63 (M+H⁺).

L-4-Trifluoromethylphenylalanine-Gabapentin (1aa): MS (ESI) m/z 385.26(M−H⁻).

L-2-Fluorophenylalanine-Gabapentin (1ab): MS (ESI) m/z 335.2 (M−H⁻),337.19 (M+H⁺).

L-3-Fluorophenylalanine-Gabapentin (1ac): MS (ESI) m/z 335.19 (M−H⁻),337.15 (M+H⁺).

L-4-Fluorophenylalanine-Gabapentin (1ad): MS (ESI) m/z 335.16 (M−H⁻),337.21 (M+H⁺).

L-2-Chlorophenylalanine-Gabapentin (1ae): MS (ESI) m/z 351.14 (M−H⁻),353.1 (M+H⁺).

L-3-Chlorophenylalanine-Gabapentin (1af): MS (ESI) m/z 351.16 (M−H⁻),353.08 (M+H⁺).

L-4-Chlorophenylalanine-Gabapentin (1ag): MS (ESI) m/z 351.15 (M−H⁻),353.1 (M+H⁺).

L-4-Bromophenylalanine-Gabapentin (1ah): MS (ESI) m/z 395.06, 397.05(M−H⁻), 397.02, 399.01 (M+H⁺).

L-4-Iodophenylalanine-Gabapentin (1ai): MS (ESI) m/z 443.01 (M−H⁻),445.16 (M+H⁺).

L-2-Methoxyphenylalanine-Gabapentin (1aj): MS (ESI) m/z 347.21 (M−H⁻).

L-4-Methoxyphenylalanine-Gabapentin (1ak): MS (ESI) m/z 347.39 (M−H⁻),349.92 (M+H⁺).

L-3-Cyanophenylalanine-Gabapentin (1al): MS (ESI) m/z 342.18 (M−H⁻),344.19 (M+H⁺).

L-4-Cyanophenylalanine-Gabapentin (1am): MS (ESI) m/z 342.2 (M−H⁻),344.09 (M+H⁺).

L-3,4-Difluorophenylalanine-Gabapentin (1an): MS (ESI) m/z 353.12(M−H⁻), 355.08 (M+H⁺).

L-3,5-Difluorophenylalanine-Gabapentin (1ao): MS (ESI) m/z 353.17(M−H⁻), 355.18 (M+H⁺).

D,L-2,4-Difluorophenylalanine-Gabapentin (1ap): MS (ESI) m/z 353.14(M−H⁻).

D,L-2,6-Difluorophenylalanine-Gabapentin (1aq): MS (ESI) m/z 353.18(M−H⁻), 355.32 (M+H⁺).

L-2,4-Dichlorophenylalanine-Gabapentin (1ar): MS (ESI) m/z 385.26,387.03 (M−H⁻), 387.47, 389.08 (M+H⁺).

L-3,4-Dichlorophenylalanine-Gabapentin (1as): MS (ESI) m/z 385.1, 387.03(M−H⁻), 387.07, 388.99 (M+H⁺).

L-Penicillamine-Gabapentin (1at): MS (ESI) m/z 301.18 (M−H⁻), 303.14(M+H⁺).

1-Aminocyclopropane-1-Carbonyl-Gabapentin (1au): MS (ESI) m/z 253.23(M−H⁻), 255.2 (M+H⁺).

1-Aminocyclohexane-1-Carbonyl-Gabapentin (1av): MS (ESI) m/z 295.24(M−H⁻), 297.25 (M+H⁺).

L-Homophenylalanine-Gabapentin (1aw): MS (ESI) m/z 331.15 (M−H⁻).

L-Serine-Gabapentin (1ax): MS (ESI) m/z 257.11 (M−H⁻), 259.10 (M+H⁺).

Preparation of Aminoacyl-Gabapentin Derivatives Method 2

To an ice-cold reaction mixture containing an N-Boc-protected amino acid(1 mmol) and triethylamine (0.278 mL, 2 mmol) in anhydrous THF (100 mL)was added ethyl chloroformate (0.115 mL, 1.2 mmol). The reaction mixturewas stirred at 0° C. for 30 min. A solution of gabapentin hydrochloridesalt (311 mg, 1.5 mmol) in 0.5 N NaOH (6 mL) was added at 0° C., stirredfor 30 min at 0° C. and then 30 min at room temperature. Afterevaporation of the THF under reduced pressure, saturated citric acid (20mL) was added. The product was extracted with ethyl acetate (3×30 mL)and the combined organic phase dried over MgSO₄ and concentrated todryness. The resulting residue was treated with 80% (v/v) TFA indichloromethane at room temperature for 30 min. The reaction mixture wasevaporated to dryness. The aminoacyl-Gabapentin product was purified bypreparative HPLC as described above.

Example 2 Preparation of Aspartyl-Gabapentin Derivatives

To a solution of Boc-Asp(OMe)-OH (5 g, 20 mmol) in acetonitrile (100 μL)was added N-hydroxysuccinimide (2.53 g, 22 mmol) andN,N-dicyclohexylcarbodiimide (4.5 g, 22 mmol). The reaction was stirredat ambient temperature for 4 h. The reaction mixture was filtereddirectly into an aqueous solution (100 mL) of gabapentin (3.77 g, 22mmol) and sodium hydrogencarbonate (1.85 g, 22 mmol) and the resultingmixture stirred at ambient temperature for 16 h. The reaction wasconcentrated under reduced pressure, the residue dissolved in ethylacetate/diethyl ether (1:1, 300 mL) and washed with 0.1M aqueouspotassium hydrogensulfate (2×500 mL). The organic phase was separated,dried over Na₂SO₄, filtered, and concentrated to dryness under reducedpressure to afford Boc-Asp(OMe)-Gabapentin as a white solid (7.8 g, 19.5mmol, 98%).

To 250 mL peptide vessel was added 2-chlorotritylchloride resin (10 g,1.69 mmol/g, 16.9 mmol), and a solution of Boc-Asp(OMe)-Gabapentin (7.8g, 19.5 mmol) in dichloromethane (125 mL). N,N-Diisopropylethylamine(5.2 mL, 30 mmol) was added and the vessel was shaken at ambienttemperature for 1 h. The resin was drained and washed consecutively withdichloromethane (3×250 μL), methanol (3×250 mL), and tetrahydrofuran(3×250 mL). The resin was shaken with lithium hydroxide (0.5 g) intetrahydrofuran (100 mL), water (10 μL), and methanol (25 mL) at ambienttemperature for 2 h. The resin was drained and washed with methanol(3×250 mL), dichloromethane (3×250 mL), and N,N-dimethylformide (3×250mL). The resin was aliquoted into 10 100 mL Alltech tubes and a solutionof HBTU (32 g, 84 mmol) in N,N-dimethylacetamide (250 mL) andN,N-diisopropylethylamine (22 mL) was distributed evenly to each vessel.

To each of the ten vessels was added 5 equivalents of one of thefollowing 10 amines: (a) pyrrolidine; (b) butylamine; (c)2-methoxyethylamine; (d) piperidine; (e) isoamylamine; (f)cyclohexylamine; (g) 4-aminomethylpyridine; (h) 3-aminomethylpyridine;(i) heptylamine; and (j) 3,4-dimethoxyphenethyl-amine. The vessels werecapped and shaken at ambient temperature for 16 h. The resins weredrained and washed with 1-methylpyrrolidinone (3×100 mL), methanol(3×100 mL), and dichloromethane (3×100 mL). The resins were each treatedwith 25% trifluoroacetic acid in dichloromethane (20 mL) for 10 minutes,and drained into 40 mL vials. The solvent was removed under reducedpressure. The residues were dissolved in acetonitrile/water (1:1, 5 mL)and filtered through a 0.2 μm nylon membrane filter. The solutions werepurified by preparative HPLC. The pure fractions were combined andconcentrated under reduced pressure. The pure compounds were redissolvedin 20% acetonitrile in water (10 mL), frozen, and lyophilized to afford15-30 mg of each of the following compounds as white powders:

L-Aspartyl-β-pyrrolidinyl)-Gabapentin (3a): MS (ESI) m/z 338.28 (M−H⁻),340.29 (M+H⁺).

L-Aspartyl-β-(Butylamido)-Gabapentin (3b): MS (ESI) m/z 340.31 (M−H⁻),342.32 (M+H⁺).

L-Aspartyl-β-(2-Methoxyethylamido)-Gabapentin (3c): MS (ESI) m/z 342.30(M−H⁻), 344.29 (M+H⁺).

L-Aspartyl-β-(Piperidinyl)-Gabapentin (3d): MS (ESI) m/z 352.32 (M−H⁻),354.31 (M+H⁺).

L-Aspartyl-β-(3-Methylbutylamido)-Gabapentin (3e): MS (ESI) m/z 354.32(M−H⁻), 356.37 (M+H⁺).

L-Aspartyl-β-(Cyclohexylamido)-Gabapentin (3f): MS (ESI) m/z 366.33(M−H⁻), 368.32 (M+H⁺).

L-Aspartyl-β-(4-Amidomethylpyridine)-Gabapentin (3g): MS (ESI) m/z375.27 (M−H⁻), 377.29 (M+H⁺).

L-Aspartyl-β-(3-Amidomethylpyridine)-Gabapentin (3h): MS (ESI) m/z375.25 (M−H⁻), 377.25 (+H⁺).

L-Aspartyl-β-(Heptylamido)-Gabapentin (3i): MS (ESI) m/z 382.32 (M−H⁻),384.42 (M+H⁺).

L-Aspartyl-β-(3,4-Dimethoxyphenethylamido)-Gabapentin (3j): MS (ESI) m/z448.23 (M−H⁻), 450.27 (M+H⁺).

L-Aspartyl-β-(O-Cyclohexyl ester)-Gabapentin (3k)

To a solution of L-Boc-Aspartyl-β-(O-Cyclohexyl ester)-OH (1 g, 3.2mmol) in acetonitrile (20 mL) was added N-hydroxysuccinamide (391 mg,3.4 mmol), and N,N-dicyclohexylcarbodiimide (702 mg, 3.4 mmol). Thereaction was shaken at ambient temperature for 4 h. The reaction wasfiltered directly into an aqueous solution (100 mL) of gabapentin (582mg, 3.4 mmol) and sodium hydrogencarbonate (286 mg, 3.4 mmol) and theresulting mixture was shaken at ambient temperature for 16 h. Thereaction was diluted with ethyl acetate/diethyl ether (1:1, 100 mL) andwashed with 0.1M aqueous potassium hydrogensulfate (2×150 mL). Theorganic phase was separated, dried over Na₂SO₄, filtered, andconcentrated to dryness under reduced pressure to afford theL-Boc-Aspartyl-β-(O-Cyclohexyl ester)-Gabapentin as a white solid. Thecompound was dissolved in 33% trifluoroacetic acid in dichloromethane(100 mL) and stirred at ambient temperature for 1 h. The solvent wasremoved under reduced pressure. The residue was dissolved inacetonitrile/water (1:1, 10 mL) and filtered through a 0.2 μm nylonmembrane filter. The solution was purified by preparative HPLC. The purefractions were combined and concentrated under reduced pressure toafford the title compound (3k) as a white powder. MS (ESI) m/z 367.39(M−H⁻), 369.81 (M+H⁺).

L-Aspartyl-β-(O-Benzyl ester)-Gabapentin (3l)

To a solution of L-Boc-Aspartyl-β-(O-Benzyl ester)-OH (1 g, 3.2 mmol) inacetonitrile (20 n-L) was added N-hydroxysuccinamide (391 mg, 3.4 mmol),and N,N-dicyclohexylcarbodiimide (702 mg, 3.4 mmol). The reaction wasshaken at ambient temperature for 4 h. The reaction was filtereddirectly into an aqueous solution (100 mL) of gabapentin (582 mg, 3.4mmol) and sodium hydrogencarbonate (286 mg, 3.4 mmol) and the resultingmixture was shaken at ambient temperature for 16 h. The reaction wasdiluted with ethyl acetate/diethyl ether (11:1, 100 mL) and washed with0.1M aqueous potassium hydrogensulfate (2×150 mL). The organic phase wasseparated, dried over Na₂SO₄, filtered, and concentrated to drynessunder reduced pressure to afford the L-Boc-Aspartyl-β-(O-Benzylester)-Gabapentin as a white solid. The compound was dissolved in 33%trifluoroacetic acid in dichloromethane (100 mL) and stirred at ambienttemperature for 1 h. The solvent was removed under reduced pressure. Theresidue was dissolved in acetonitrile/water (1:1, 10 mL) and filteredthrough a 0.2 μm nylon membrane filter. The solution was purified bypreparative HPLC. The pure fractions were combined and concentratedunder reduced pressure to afford the title compound (3l) as a whitepowder. MS (ESI) m/z 375.28 (M−H⁻), 377.65 (M+H⁺).

Example 3 Preparation of Tyrosine-Gabapentin Derivatives

To a solution of Boc-Tyr-OH (4.2 g, 15 mmol) in acetonitrile (100 mL)was added N-hydroxysuccinamide (1.84 g, 16 mmol) andN,N-dicyclohexylcarbodiimide (3.3 g, 16 mmol). The reaction was stirredat ambient temperature for 2 h. The reaction mixture was filtereddirectly into an aqueous solution (100 mL) of gabapentin (2.7 g, 16mmol) and sodium hydroxide (640 mg, 16 mmol), and the resulting mixturestirred at ambient temperature for 16 h. The reaction was concentratedunder reduced pressure, the residue was dissolved in ethylacetate/diethyl ether (1/1, 200 mL) and washed with 0.1M aqueouspotassium hydrogensulfate (2×200 mL). The organic phase was separated,dried over Na₂SO₄, filtered, and concentrated to dryness under reducedpressure to afford Boc-Tyr-Gabapentin as a white solid (7.4 g, 16 mmol).

Boc-Tyr-Gabapentin (434 mg, 1 mmol) was treated with trifluoroaceticacid (10 mL) at ambient temperature for 1 h, followed by the addition ofan acid chloride, symmetrical anhydride or chloroformate (0.9 mmol). Thereactions were stirred at ambient temperature for 1 h. The solvent wasremoved under reduced pressure and the residues dissolved inacetonitrile/water (1:1, 5 mL) and filtered through a 0.2 μm nylonmembrane filter. The solutions were purified by preparative HPLC. Thepure fractions were combined and concentrated under reduced pressure toafford each of the following compounds as colorless syrups:

L-Tyrosine-(O-2,6-Dimethylbenzoyl)-Gabapentin (4a): MS (ESI) m/z 465.33(M−H⁻), 467.33 (M+H⁺).

L-Tyrosine-(O-2,6-Dimethoxybenzoyl)-Gabapentin (4b): MS (ESI) m/z 497.34(M−H⁻), 499.30 (M+H⁺).

L-Tyrosine-(O-2-Methylbenzoyl)-Gabapentin (4c): MS (ESI) m/z 451.31(M−H⁻), 453.35 (M+H⁺).

L-Tyrosine-(O-2-Bromobenzyloxycarbonyl)-Gabapentin (4d): MS (ESI) m/z544.12, 546.14 (M−H⁻), 546.15, 548.16 (M+H⁺).

Example 4 Preparation of L-4-Bromophenylalanine-Pregabalin (5)

A suspension of L-Boc-4-bromophenylalanine (500 mg, 1.46 mmol),N-hydroxysuccinimide (173 mg, 1.50 mmol), N,N-dicyclohexylcarbodiimide(310 mg, 1.50 mmol) in acetonitrile was stirred at room temperature for1 h. Then the reaction mixture was filtered directly into a stirredaqueous solution of pregabalin (239 mg, 1.50 mmol) and NaOH (60 mg, 1.5mmol). The resulting mixture was stirred for another hour at roomtemperature. After removing the organic solvent under reduced pressure,the aqueous solution was acidified to pH 3 with KHSO₄ and the resultingmixture was extracted with ethyl acetate:ether (1:2). The organicextract was washed with brine and dried over Na₂SO₄. After removing thesolvent under reduced pressure, the residue was dissolved in 4N HCl indioxane (10 mL) and stirred at room temperature for 2 h. The solutionwas concentrated under reduced pressure to afford white precipitate.Re-crystallization from hot water followed by HPLC purification afforded412 mg of the title compound (5). ¹H-NMR (CD₃OD, 400 MHz): δ 0.86 (d,J=6.8 Hz, 3H), 0.89 (d, J=6.8 Hz, 3H), 1.06 (m, 2H), 1.64 (m, 1H),2.08-2.00 (m, 3H), 3.00 (m, 2H), 3.12 (dd, J=14.0, 7.4 Hz, 1H), 3.25(overlapped with methanol, 1H), 3.95 (m, 1H), 7.19 (d, J=8.0 Hz, 2H),7.50 (d, J=8 Hz, 2M).

Example 5 In Vitro Compound Transport Assays with PEPT1 andPEPT2-Expressing Cell Lines (a) Inhibition of Radiolabeled Gly-SarUptake

Rat and human PEPT1 and PEPT2 expressing CHO cell lines were prepared asdescribed in PCT Application WO01/20331. Gabapentin-containingdipeptides were evaluated for interaction with the peptide transportersusing a radiolabeled substrate uptake assay in a competitive inhibitionformat, as described in PCT Application WO01/20331. Transport-inducedcurrents were also measured in Xenopus oocytes transfected with rat andhuman PEPT1 and PEPT2.

(b) Analysis of Electrogenic Transport in Xenopus Oocytes

RNA preparation: Rat and human PFPT1 and PEPT2 transporter cDNAs weresubcloned into a modified pGEM plasmid that contains 5′ and 3′untranslated sequences from the Xenopus β-actin gene. These sequencesincrease RNA stability and protein expression. Plasmid cDNA waslinearized and used as template for in vitro transcription (EpicentreTechnologies transcription kit, 4:1 methylated:non-methylated GTP).

Xenopus oocyte isolation. Xenopus laevis frogs were anesthetized byimmersion in Tricaine (1.5 g/mL in deionized water) for 15 min. Oocyteswere removed and digested in frog ringer solution (90 mM NaCl, 2 mM KCl,1 mM MgCl₂, 10 mM NaHEPES, pH 7.45, no CaCl₂) with 1 mg/mL collagenase(Worthington Type 3) for 80-100 min with shaking. The oocytes werewashed 6 times, and the buffer changed to frog ringer solutioncontaining CaCl₂ (1.8 mM). Remaining follicle cells were removed ifnecessary. Cells were incubated at 16° C., and each oocyte injected with10-20 μg RNA in 45 μL solution.

Electrophysiology measurements. Transport currents were measured 2-14days after injection, using a standard two-electrode electrophysiologyset-up (Geneclamp 500 amplifier, Digidata 1320/PCLAMP software andADInstruments hardware and software were used for signal acquisition).Electrodes (2-4 mΩ) were microfabricated using a Sutter Instrumentpuller and filled with 3M KCl. The bath was directly grounded(transporter currents were less than 0.3 μA). Bath flow was controlledby an automated perfusion system (ALA Scientific Instruments, solenoidvalves).

For transporter pharmacology, oocytes were clamped at −60 to −90 mV, andcontinuous current measurements acquired using PowerLab Software and anADInstruments digitizer. Current signals were lowpass filtered at 20 Hzand acquired at 4-8 Hz. All bath and drug-containing solutions were frogringers solution containing CaCl₂. Drugs were applied for 10-30 secondsuntil the induced current reached a new steady-state level, followed bya control solution until baseline currents returned to levels thatpreceded drug application. The difference current (baseline subtractedfrom peak current during drug application) reflected the net movement ofcharge resulting from electrogenic transport and was directlyproportional to transport rate. Recordings were made from a singleoocyte for up to 60 min, enabling 30-40 separate compounds to be testedper oocyte. Compound-induced currents were saturable and gavehalf-maximal values at substrate concentrations comparable to radiolabelcompetition experiments. To compare results between oocytes expressingdifferent levels of transport activity, a saturating concentration ofglycyl-sarcosine (1 mM) was used as a common reference to normalizeresults from test compounds. Using this normalization procedure I_(max)(i.e. maximal induced current) for different compounds tested ondifferent oocytes could be compared.

Each of the compounds (1a)-(1ax), (3a)-(3l) and (5) elicitedPEPT-specific currents significantly above background (at least 5% ofI_(max) for Gly-Sar) when tested at 1 mM on oocytes expressing eitherPEPT1 or PEPT2, confining that these compounds serve as substrates forboth of these transporters.

Example 6 In Vitro Enzymatic Release of Gabapentin fromAminoacyl-Gabapentin Conjugates

The stability of aminoacyl-gabapentin conjugates was evaluated byincubating the conjugates in the various tissue and enzyme-containingpreparations listed in Table 1 below.

Tissue homogenates and plasma samples were obtained from commercialsources (Pel-Freez Biologicals, Rogers, AR, and GenTest Corporation,Woburn, Mass.). Stability of prodrugs toward the specific enzymeaminopeptidase was also evaluated by incubation with the purifiedenzyme. Experimental conditions used for the in vitro studies were asfollows. Each preparation was incubated with test compound at 37° C. forone hour. Aliquots (50 μL) were removed at 0, 30, and 60 min andquenched with 0.1% trifluoroacetic acid in acetonitrile. Samples werethen centrifuged and analyzed for the presence of prodrug and releasedgabapentin by LC/MS/MS as described below.

Rat intestinal wash is obtained from rats post-morten by rinsing thesurgically separated in testing with small volumes (about 3 mL) ofbuffered saline.

Concentrations of prodrug or gabapentin in tissue extracts weredetermined by direct injection onto an API 2000 LC/MS/MS equipped withan Agilent 1100 binary pump and autosampler Separation was achievedusing a 3.5 μm Zorbax Ellipse XDB-C8 4.4×150 mm column heated to 45° C.during the analysis. The mobile phases were: 0.1% formic acid in water(A) and 0.1% formic acid in acetonitrile (B). The gradient conditionwas: 2% B for 0.5 min, increasing to 90% B in 2.0 min, maintained for2.5 min and returning to 2% B for 2 min. A TurboIonSpray source was usedon the API 2000. The analysis was performed in the positive ion mode andMRM transitions of 172.0/137.2 were used in the analysis of gabapentin(2). Ten microliters of the sample extracts were injected. Peaks wereintegrated using Analyst quantitation software. The method was linearfor (2) over the concentration range 0.002 to 2.5 μg/mL respectively.

The stability of gabapentin-containing prodrugs to Caco-2 homogenateswas evaluated as follows:

Caco-2 Homogenate S9 Stability: Caco-2 cells were grown for 21 daysprior to harvesting. Culture medium was removed and cell monolayers wererinsed and scraped off into ice-cold 10 mM sodium phosphate/0.15 Mpotassium chloride, pH 7.4. Cells were lysed by sonication at 4° C.using a probe sonicator. Lysed cells were then transferred into 1.5 mLcentrifuge vials and centrifuged at 9000 g for 20 min at 4° C. Theresulting supernatant (Caco-2 cell homogenate S9 fraction) was aliquotedinto 0.5 mL vials and stored at −80° C. until used.

For stability studies, prodrug (5 μM) was incubated in Caco-2 homogenateS9 fraction (0.5 mg protein per mL) for 60 min at 37° C. Concentrationsof intact prodrug and released drug were determined at zero time and 60minutes using LC/MS/MS.

Aminopeptidase Stability: Aminopeptidase 1 (Sigma catalog #A-9934) wasdiluted in deionised water to a concentration of 856 units/mL. Stabilitystudies were conducted by incubating prodrug (5 μM) with 0.856 units/mLaminopeptidase 1 in 50 mM Tris-HCl buffer at pH 8.0 and 37° C.Concentrations of intact prodrug and released drug were determined atzero time and 60 minutes using LC/MS/MS.

TABLE 1 Experimental Conditions for In Vitro Enzymatic Release ofGabapentin in 60 minutes from Aminoacyl-Gabapentin Prodrugs SubstratePreparation Concentration Cofactors Rat Plasma 2.0 μM None Human Plasma2.0 μM None Rat Liver S9 2.0 μM NADPH (0.5 mg/mL) Human Liver 2.0 μMNADPH S9 (0.5 mg/mL) Human 2.0 μM NADPH Intestine S9 (0.5 mg/mL) RatIntestinal 5.0 μM None Wash Caco-2 5.0 μM None Homogenate Amino- 5.0 μMNone peptidase

Each of the compounds (1 h)-(1aw) showed either partial or completeconversion to gabapentin (2) when treated with either Caco-2 homogenateor aminopeptidase under the conditions described above.

Incubation with Caco-2 homogenate for 1 hour resulted in metabolismof >50% of the following compounds (% of prodrug surviving intact inparenthesis): (1l) (29%); (1al) (46%); (1ao) (48%); (4d) (3%).

Incubation with Caco-2 homogenate for 1 hour resulted in metabolism of<50% of the following compounds (% of prodrug surviving intact inparenthesis): (1aa) (97%); (1ah) (79%); (1am) (90%); (1ap) (90%).

Example 7 Uptake of Gabapentin (2) Following Oral Administration ofProdrugs to Rats

The pharmacokinetics of the prodrugs prepared in Examples 1 and 3 wereexamined in rats. Three groups of four male Sprague-Dawley rats (approx200 g) with jugular cannulae each received one of the followingtreatments: A) a single bolus intravenous injection of gabapentin (25mg/kg, as a solution in water); B) a single oral dose of gabapentin (25mg/kg, as a solution in water) administered by oral gavage; C) a singleoral dose of prodrug (25 mg-equivalents of gabapentin per kg bodyweight, as a solution in water) administered by oral gavage. Animalswere fasted overnight prior to dosing and until 4 hours post-dosing.Serial blood samples were obtained over 24 hours following dosing andblood was processed for plasma by centrifugation. Plasma samples werestored at −80° C. until analyzed.

Concentrations of prodrug or gabapentin in plasma samples weredetermined by LC/MS/MS as described above. Plasma (50 μL) wasprecipitated by addition of 100 mL of methanol and supernatant wasinjected directly onto the LC/MS/MS system. Following oraladministration of gabapentin, concentrations of gabapentin in plasmareached a maximum plasma concentration (C_(max)) of 10.3 μg/mL anddeclined thereafter with a terminal half-life of 2.4±0.5 hours. The oralbioavailability of gabapentin was 87±18%. Following oral administrationof gabapentin prodrugs, concentrations of prodrug and gabapentin inplasma were monitored over 24 hours. The C_(max) values for prodrug(C_(max) PD) were as follows:

(1l) C_(max) PD=0.5 μg/mL

(1al) C_(max) PD=0.6 μg/mL

(1ao) C_(max) PD=2.9 μg/mL

(4d) C_(max) PD=<0.004 μg/mL

(1aa) C_(max) PD=30.0 μg/mL

(1ah) C_(max) PD=103 μg/mL

(1am) C_(max) PD22.4 μg/mL

(1ap) C_(max) PD 278 μg/mL

This data indicates that gabapentin prodrugs which undergo substantial(i.e. >50%) degradation in the presence of enterocyte (Caco-2)homogenate over a period of 1 h in vitro (e.g. (1l), (1al), (1ao) and(4d)) produce low maximal plasma prodrug concentrations following oraladministration to rats. This is likely due to presystemic hydrolysis (orother metabolism) of the prodrug, either within the intestinal lumen, atthe enterocyte brush-border membrane or intracellularly (withinenterocytes lining the GI tract).

The C_(max) value for gabapentin following oral administration of (1ah)was 6.1 μg/mL, and its oral bioavailability (F) as gabapentin was 53%.Prodrugs of gabapentin have an oral bioavailability (F) as gabapentinpreferably of at least 40%, more preferably of at least 50%, and mostpreferably of at least 75%.

Example 8 Uptake of Gabapentin (2) Following Oral Administration of(1ax) to Monkeys and Rats

The pharmacokinetics of prodrug (1ax) was examined in adult malecynomologous monkeys. The prodrug was administered orally to four adultmale monkeys (approximate body weight of 6.5 kg) via an oral nasogastrictube as solutions in water or PEG 400. The dose was 1.0 or 75mg-equivalents of gabapentin per kg body weight. Animals were fastedovernight before the study and for 4 hours post-dosing. Blood samples(1.0 mL) were obtained via femoral or cephalic venipuncture at intervalsover 48 hours after oral dosing. Blood was processed immediately forplasma and plasma was frozen at −80° C. until analyzed. Concentrationsof (1ax) or gabapentin (2) in plasma samples were determined by LC/MS/MSas previously described, using MRM transitions of 259.20/154.00 foranalysis of (1ax). Oral bioavailability was determined by comparison ofarea under the gabapentin concentration versus time curve (AUC)following oral administration of prodrug or intravenous administrationof an equimolar dose of gabapentin hydrochloride. The C_(max) and AUCvalues for gabapentin (2) (C_(max) G; AUC G), and the oralbioavailability as gabapentin (F) for each treatment were as follows:

(2) at 10 mg-eg/kg: C_(max) G=3.7±1.6 μg/mL, AUC G=32.1±10.4 μg/mL;F=53.9±17.3%.

(1ax) at 10 mg-eg/kg: C_(max) G=3.7±1.1 μg/mL; AUC G=24.7±7.3 μg/mL;F=41.5±12.2%.

(2) at 75 mg-eg/kg: C_(max) G=10.8±1.3 μg/mL; AUC G=102±4.9 μg/mL;F=22.9±1.1%.

(1ax) at 75 mg-eg/kg: C_(max) G=14.5±1.6 μg/mL; AUC G=125±5.0 μg/mL;F=28.1±1.1%.

This data shows a statistically significant increase (p<0.05) in bothC_(max) and AUC for gabapentin after oral administration as the prodrug(1ax), as compared to dosing of an equimolar amount of gabapentin (2)itself at the high dose (75 mg-eq./kg) level. A 7.5-fold increase ingabapentin dose results in only a 3.2-fold increase in gabapentinexposure (as measured by AUC), while a 7.5-fold increase in prodrug doseresults in a 5.1-fold increase in gabapentin exposure (as measured byAUC). Thus the less than dose-proportional increase in gabapentinexposure observed following gabapentin dosing at levels sufficient tosaturate the drug's normal uptake pathway can be offset, in part, byadministering a prodrug that exploits a higher capacity uptake mechanism(e.g. the PEPT transporter).

However, oral and i.v. dosing of prodrug (1ax) to rats has demonstratedthat the fraction of (1ax) absorbed intact following oral administrationis only about 15-20%, indicating that the majority of the prodrug ishydrolyzed to gabapentin presystemically (probably within the intestinallumen). This presystemically generated gabapentin is subject toabsorption via the same saturable pathway normally used by gabapentin.This data is consistent with the less than full dose-proportionalincrease in gabapentin exposure observed following prodrug (1ax) doseascension in monkeys, since it is likely that only a fraction of theprodrug survived intra-lumenally to take advantage of a higher capacityuptake pathway via the peptide transporter.

In contrast to (1ax), oral and i.v. dosing of prodrug (1ah) to rats hasdemonstrated that the fraction of (1ah) absorbed intact following oraladministration is about 60%, with the prodrug converting rapidly to (2)within the systemic circulation and providing gabapentin with an oralbioavailability of about 53%. Thus the 4-bromophenylalanine-containinggabapentin dipeptide is a more preferred prodrug than the serinecompound for exploiting the greater uptake capacity of intestinalpeptide transporters.

Example 9 Uptake of Gabapentin (2) Following Oral Administration of(1ah) to Monkeys

The pharmacokinetics of the prodrug (1ah) was examined in adult malecynomologous monkeys. The prodrug was administered as its sodium saltorally to four adult male monkeys (approximate body weight of 6.5 kg)via an oral nasogastric tube as solutions in water. The dose was 10mg-equivalents of gabapentin per kg body weight. Animals were fastedovernight before the study and for 4 hours post-dosing. Blood samples(1.0 mL) were obtained via femoral or cephalic venipuncture at intervalsover 48 hours after oral dosing. Blood was processed immediately forplasma and plasma was frozen at −80° C. until analyzed. Concentrationsof (1ah) and (2) in plasma samples were determined by LC/MS/MS aspreviously described, using MRM transitions of 399.07/200.02 foranalysis of (1ah). Oral bioavailability was determined by comparison ofarea under the gabapentin concentration versus time curve (AUC)following oral administration of prodrug or intravenous administrationof an equimolar dose of gabapentin hydrochloride. Pharmacokineticparameters for (1ah) were as follows:

C_(max) G=3.8±1.1 μg/mL; AUC G=29.1±3.5 μg/mL; C_(max) PD=14.9±5.3μg/mL; AUC PD=18.9±6.5 μg/mL; F=49.1±6.8%.

This data corroborates in monkeys the finding from rats that (1 ah) iseffectively absorbed intact after oral dosing and undergoes rapidconversion to gabapentin.

Example 10 Uptake of Gabapentin Following Administration of Gabapentinor Prodrug (1ah) Intracolonically in Rats

Sustained release oral dosage forms, which release drug slowly overperiods of 6-24 hours, generally release a significant proportion of thedose within the colon. Thus drugs suitable for use in such dosage formspreferably exhibit good colonic absorption. This experiment wasconducted to assess the suitability of a gabapentin prodrug ((1ah)) foruse in an oral sustained release dosage form.

Rats were obtained commercially and were pre-cannulated in the both theascending colon and the jugular vein. Animals were conscious at the timeof the experiment. All animals were fasted overnight and until 4 hourspost-dosing. Gabapentin or (1ah) (as the sodium salt) were administeredas solutions in water directly into the colon via the cannula at a doseequivalent to 25 mg of gabapentin per kg. Blood samples (0.5 mL) wereobtained from the jugular cannula at intervals over 8 hours and werequenched immediately by addition of acetonitrile/methanol to preventfurther conversion of the prodrug. Blood was processed for plasma bycentrifugation and concentrations of prodrug (1ah) or (2) in plasmasamples were determined by LC/MS/MS as previously described. Followingcolonic administration of (1ah) the maximum plasma concentrations ofgabapentin, as well as the area under the gabapentin plasmaconcentration vs. time curves, were significantly greater (>3-fold) thanthat produced from colonic administration of gabapentin itself.

This data demonstrates that compounds of the invention may be formulatedas compositions suitable for enhanced absorption and/or effectivesustained release of GABA analogs to minimize dosing frequency due torapid systemic clearance of these GABA analogs.

1-50. (canceled)
 51. A compound having the formula

and pharmaceutically acceptable salts thereof, wherein: D is a moietyselected from the group consisting of the following GABA analogmoieties:

R³ is a covalent bond; R¹¹ is —COOH; and R⁵⁶ is substituted arylalkyl;with the proviso that R⁵⁶ is not 4-bromophenylmethyl.
 52. A compoundhaving the formula

and pharmaceutically acceptable salts thereof, wherein: D is a moietyselected from the group consisting of the following GABA analogmoieties:

R³ is a covalent bond; R¹¹ is —COOH; and R⁵⁶ is substituted arylalkyl;with the proviso that R⁵⁶ is not 4-bromophenylmethyl; and provided thatthe compound has a half-life of at least 1 hour when incubated in vitroat 37° C. at a concentration of 5 μM with an S9 fraction of Caco-2 cellhomogenate at a protein concentration of 0.5 mg/mL.
 53. The compound ofany one of claims 51 and 52, wherein R⁵⁶ is selected from the groupconsisting of 2-methylphenylmethyl, 3-methylphenylmethyl,4-methylphenylmethyl, 2-methoxyphenylmethyl, 3-methoxyphenylmethyl,4-methoxyphenylmethyl, 2-trifluoromethylphenylmethyl,3-trifluoromethylphenylmethyl, 4-trifluoromethylphenylmethyl,2-cyanophenylmethyl, 3-cyanophenylmethyl, 4-cyanophenylmethyl,2-fluorophenylmethyl, 3-fluorophenylmethyl, 4-fluorophenylmethyl,2-chlorophenylmethyl, 3-chlorophenylmethyl, 4-chlorophenylmethyl,2-bromophenylmethyl, 3-bromophenylmethyl, 2-iodophenylmethyl,3-iodophenylmethyl, 4-iodophenylmethyl, 2,3-difluorophenylmethyl,2,4-difluorophenylmethyl, 2,5-difluorophenylmethyl,2,6-difluorophenylmethyl, 3,4-difluorophenylmethyl,3,5-difluorophenylmethyl, 2,3-dichlorophenylmethyl,2,4-dichlorophenylmethyl, 2,5-dichlorophenylmethyl,2,6-dichlorophenylmethyl, 3,4-dichlorophenylmethyl, and3,5-dichlorophenylmethyl.
 54. The compound of any one of claims 51 and52, wherein R⁵⁶ is selected from 4-trifluorophenylmethyl, 4-cyanophenyl,and 2,4-difluorophenyl.
 55. The compound of claim 51, which upon oraladministration to a patient in need of therapy, provides therapeuticallyefficacious levels of a GABA analog in the plasma of the patient, wherethe GABA analog in the plasma of the patient has a concentration whichover time provides a curve of concentration of the GABA analog in theplasma over time, the curve having an area under the curve (AUC) or amaximum plasma concentration (C_(max)) which is substantially moreproportional to the dose of GABA analog administered, as compared to theproportionality achieved following oral administration of the GABAanalog itself.
 56. The compound of claim 51, which is metabolized toproduce a GABA analog at a sufficient rate in vivo, upon colonicadministration to rats, to produce a C_(max) or an AUC of the GABAanalog in plasma of at least 200% of the C_(max) or an AUC of the GABAanalog in plasma achieved by colonically administering an equimolar doseof the GABA analog itself.
 57. A pharmaceutical composition comprising atherapeutically effective amount of a compound according to claim 51 anda pharmaceutically acceptable carrier.
 58. An oral dosage formcomprising: a sustained release oral dosage form containing a compoundof claim 51, the dosage form being adapted for oral delivery to apatient; the dosage form further being adapted to release the compoundgradually into the intestinal lumen of the patient over a period afteroral administration.
 59. The dosage form of claim 58, wherein the periodcomprises at least about 6 hours.
 60. The dosage form of claim 58,wherein the dosage form releases from 0 to 20% of a compound in 0 to 2hours, from 20 to 50% of the compound in 2 to 12 hours, from 50 to 85%of the compound in 3 to 20 hours and greater than 75% of the compound in5 to 18 hours.
 61. The dosage form of claim 58, wherein the dosage formcomprises an osmotic dosage form, a compound-releasing polymer, acompound-releasing lipid, a compound-releasing wax, tiny timed-releasepills, or compound-releasing beads.
 62. A method for achieving sustainedrelease of a GABA analog in a patient in need of therapy with the GABAanalog, comprising orally administering to the patient a sustainedrelease dosage form containing a therapeutically effective amount of thecompound of claim
 51. 63. A method for treating epilepsy, depression,anxiety, or psychosis, pain in a patient, comprising administering to apatient in need of such treatment a therapeutically effective amount ofthe oral dosage form of claim 58.